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Do Angiotensin II Receptor Blockers (ARBs) or other factors control the level of ACE2 expression? [coronavirus receptor]

Do Angiotensin II Receptor Blockers (ARBs) or other factors control the level of ACE2 expression? [coronavirus receptor]


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Because ACE2 is used by SARS-NCoV-2 to enter the cell, I am curious what factors determine its expression. Interestingly, myocardial infarction increases ACE2 expression in the heart in an animal model ( https://www.ncbi.nlm.nih.gov/pubmed/15671045 ). The paper found no significant effect from ramipril, an ACE inhibitor, but I don't think I can assume ARBs would work the same way. (I am suspicious they might increase it based on the increase in the product Ang(1-7) level - https://www.nature.com/articles/hr200974 ) Note that soluble sACE2 can bind cells that did not produce it, by an RGD independent association with integrin beta 1.

Anything that influences the amount of ACE2 on cell surfaces is a useful answer.


I should follow up with some things I've found. As a starting point, the normal expression pattern is available at https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1570 - note the staining of simple squamous epithelium in the alveoli and the endothelia of blood vessels. Another paper details a sharp decrease in expression with age in rats, but I don't know if that extends to humans.

For regulation of expression, I was surprised to see that Google Scholar actually provides a very good assortment of search results, easier to work with than PubMed, which were topped by the MI regulation I described in the question. Additionally https://onlinelibrary.wiley.com/doi/abs/10.1002/path.1670 (yes, that IS a different link) describes ACE2 expression in renal disease but not in normal kidney. ACE2 expression correlated with proteinuria, but negatively with GFR. https://link.springer.com/article/10.1007/s00125-008-0988-x There are discordant notes in some other situations: for example, subtotal nephrectomy decreased ACE2 expression in a way that was partially prevented by ramipril. https://portlandpress.com/clinsci/article/118/4/269/68827/Reduction-in-renal-ACE2-expression-in-subtotal

The mRNA and protein are both described in atherosclerotic lesions: https://onlinelibrary.wiley.com/doi/abs/10.1002/path.2357

In the lungs https://jvi.asm.org/content/79/23/14614.short describes a positive correlation with differentiation state in airway epithelium. The regulation by HIF-1 alpha in hypoxia seems of special importance: https://journals.physiology.org/doi/full/10.1152/ajplung.90415.2008 but it is complicated (both positive and negative).

ACE2 is also expressed at high levels in placenta during pregnancy - at least in rats. https://journals.physiology.org/doi/full/10.1152/ajpregu.90592.2008

Last but not least, pharmacologic data is reviewed at https://link.springer.com/content/pdf/10.1007/s11906-008-0076-0.pdf which describes up-regulation of ACE2 by angiotensin II receptor blockers, ACE blockers, and mineralocorticoid receptor blockers. This includes the common drugs lisinopril and losartan. (see also https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.12573 ) Unfortunately the paper did not report substances inhibiting ACE2 expression. But https://journals.physiology.org/doi/full/10.1152/ajpheart.00239.2008 reported that high glucose (!) or PKC inhibitors could reduce ACE2 expression. (but the high glucose was causing kidney injury, which as described above could mean more ACE2… ) The anti-diabetes drug liraglutide increased ACE2: https://academic.oup.com/endo/article/156/10/3559/2422879 To top it all off? SARS itself decreases ACE2 expression, and this might be part of the process injuring the lungs: https://www.nature.com/articles/nm1267

This is by no means a complete survey, and there is much I don't understand. The relationship between ACE2 biology and the emerging COVID-19 risk groups seems apparent - as is the urgent need for research to determine which manipulations to ACE2 expression have positive versus negative effects on the prognosis of that disease.

Update: a NEJM podcast today described this biology as 'complicated' link. It is clearly of interest, but still under investigation. For example, losartan is presently the subject of two clinical studies news, presumably these ClinicalTrials


Perhaps take a look at the GeneCards record for ACE2 (https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE2), which contains annotations for regulatory regions (e.g., enhancers and promoters) which contain transcription factor binding sites. TFs could potentially bind to these regions to regulate the expression of this target. ChIP-seq data can help lend experimental support.


Over-expression of ACE2 in case of ACE inhibition has been found: Carlos M Ferrario et al., Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2, https://pubmed.ncbi.nlm.nih.gov/15897343/

These findings seem to be confirmed by findings that vice versa, in the opposite situation of high levels of AngiotensinII downregulation of ACE2 occurs:

Deshotels MR, Xia H, Sriramula S, Lazartigues E, Filipeanu CM: Angiotensin-II mediates angiotensin converting enzyme type 2 internalization and degradation through an Angiotensin-II type I receptor-dependent mechanism. Hypertension 2014; 64: 1368-75 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231883/

Two studies, however, apparently did not find any down- or upregulation, which is in line with the reference you cited:

  1. Ramchand J, Patel SK, et al., Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. Plos One 2018; 13: e0198144
  2. Walters TE, Kalman JM, et al., Angiotensin converting enzyme 2 activity and human atrial fibrillation (… ) Europace 2017; 19 (8): 1280-7

As your question seems to be unsettled here is my individual opinion:

The feedback circle you suggest makes sense as a mechanism of upregulation (more product leads to more production). Why not have more input if output can be made and has been generated in larger and larger amounts? However, there also is "demand or no demand" down the cascade. A large amount of product that accumulates thus may signal a lack of its being needed - I'd cast my vote for down-regulation of the expression of input receptors, as I'd vote for "we have enough". So contrary to your answering your question I'd suggest a high amount of product Angotensin (1-7) might cause a down-, not upregulation of ACE2.

Over-expression of receptors, to my knowledge, explains drug addiction and getting used to medication.

If in surplus of ligand hormone (in that case Angiotensin II) all receptors are "filled", it makes sense to broaden the basis and up regulate expression of ACE2. Thus, a block of ACE (not ACE2!) by ace-inhibitors would not lead to overexpression which seems coherent with the results of the study on blood pressure medication you cited.

Interestingly, there is an alternative pathway of ligand transformation, and an alternative product of ACE2, it's Angiotensin (1-9). It think it is a possibility that those ACE2 cells do over-express that are engaged in the modification of AT 1-9, not AT II, as ACE-inhibitors ("beta blockers" in German) do not address or inhibit renin production which should remain elevated. Renin becomes Angiotensin I, the alternative ligand of ACE2. However, downward that alternativ pathway, it's ACE again that transforms, and its being inhibited dampens "demand".


What is the ACE2 receptor?

In the search for treatments for COVID-19, many researchers are focusing their attention on a specific protein that allows the virus to infect human cells. Called the angiotensin-converting enzyme 2, or ACE2 &ldquoreceptor,&rdquo the protein provides the entry point for the coronavirus to hook into and infect a wide range of human cells. Might this be central in how to treat this disease?

We are scientists with expertise in pharmacology, molecular biology and biochemistry, with a strong commitment to applying these skills to the discovery of novel therapies for human disease. In particular, all three authors have experience studying angiotensin signaling in various disease settings, a biochemical pathway that appears to be central in COVID-19. Here are some of the key issues to understand about why there&rsquos so much focus on this protein.

What is the ACE2 receptor?

ACE2 is a protein on the surface of many cell types. It is an enzyme that generates small proteins &ndash by cutting up the larger protein angiotensinogen &ndash that then go on to regulate functions in the cell.

Using the spike-like protein on its surface, the SARS-CoV-2 virus binds to ACE2 &ndash like a key being inserted into a lock &ndash prior to entry and infection of cells. Hence, ACE2 acts as a cellular doorway &ndash a receptor &ndash for the virus that causes COVID-19.

Where in the body is it found?

ACE2 is present in many cell types and tissues including the lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract. It is present in epithelial cells, which line certain tissues and create protective barriers.

The exchange of oxygen and carbon dioxide between the lungs and blood vessels occurs across this epithelial lining in the lung. ACE2 is present in epithelium in the nose, mouth and lungs. In the lungs, ACE2 is highly abundant on type 2 pneumocytes, an important cell type present in chambers within the lung called alveoli, where oxygen is absorbed and waste carbon dioxide is released.

What is the normal role ACE2 plays in the body?

ACE2 is a vital element in a biochemical pathway that is critical to regulating processes such as blood pressure, wound healing and inflammation, called the renin-angiotensin-aldosterone system (RAAS) pathway.

ACE2 helps modulate the many activities of a protein called angiotensin II (ANG II) that increases blood pressure and inflammation, increasing damage to blood vessel linings and various types of tissue injury. ACE2 converts ANG II to other molecules that counteract the effects of ANG II.

Of greatest relevance to COVID-19, ANG II can increase inflammation and the death of cells in the alveoli which are critical for bringing oxygen into the body these harmful effects of ANG II are reduced by ACE2.

When the SARS-CoV-2 virus binds to ACE2, it prevents ACE2 from performing its normal function to regulate ANG II signaling. Thus, ACE2 action is &ldquoinhibited,&rdquo removing the brakes from ANG II signaling and making more ANG II available to injure tissues. This &ldquodecreased braking&rdquo likely contributes to injury, especially to the lungs and heart, in COVID-19 patients.

Does everyone have the same number of ACE2 on their cells?

No. ACE2 is present in all people but the quantity can vary among individuals and in different tissues and cells. Some evidence suggests that ACE2 may be higher in patients with hypertension, diabetes and coronary heart disease. Studies have found that a lack of ACE2 (in mice) is associated with severe tissue injury in the heart, lungs and other tissue types.

Does the quantity of receptors determine whether someone gets more or less sick?

This is unclear. The SARS-CoV-2 virus requires ACE2 to infect cells but the precise relationship between ACE2 levels, viral infectivity and severity of infection are not well understood.

Even so, aside from its ability to bind the SARS-CoV-2 virus, ACE2 has protective effects against tissue injury, by mitigating the pathological effects of ANG II.

When the amount of ACE2 is reduced because the virus is occupying the receptor, individuals may be more susceptible to severe illness from COVID-19. That is because enough ACE2 is available to facilitate viral entry but the decrease in available ACE2 contributes to more ANG II-mediated injury. In particular, reducing ACE2 will increase susceptibility to inflammation, cell death and organ failure, especially in the heart and the lung.

Which organs are most severely damaged by SARS-CoV-2?

The lungs are the primary site of injury by SARS-CoV-2 infection, which causes COVID-19. The virus reaches the lungs after entry in the nose or mouth.

ANG II drives lung injury. If there is a decrease in ACE2 activity (because the virus is binding to it), then ACE2 can&rsquot break down the ANG II protein, which means there is more of it to cause inflammation and damage in the body.

The virus also impacts other tissues that express ACE2, including the heart, where damage and inflammation (myocarditis) can occur. The kidneys, liver and digestive tract can also be injured. Blood vessels may also be a site for damage.

In a recent research paper, we argued that a key factor that determines severity of damage in patients with COVID-19 is abnormally high ANG II activity.

What are ACE inhibitors? Are they a possible treatment or prophylactic for SARS-CoV-2?

Angiotensin converting enzyme (ACE, aka ACE1) is another protein, also found in tissues such as the lung and heart, where ACE2 is present. Drugs that inhibit the actions of ACE1 are called ACE inhibitors. Examples of these drugs are ramipril, lisinopril, and enalapril. These drugs block the actions of ACE1 but not ACE2. ACE1 drives the production of ANG II. In effect, ACE1 and ACE2 have a &ldquoyin-yang&rdquo relationship ACE1 increases the amount of ANG II, whereas ACE2 reduces ANG II.

By inhibiting ACE1, ACE inhibitors reduce the levels of ANG II and its ability to increase blood pressure and tissue injury. ACE inhibitors are commonly prescribed for patients with hypertension, heart failure and kidney disease.

Another commonly prescribed class of drugs, angiotensin receptor blockers (ARBs, e.g., losartan, valsartan, etc.) have similar effects to ACE inhibitors and may also be useful in treating COVID-19.

Evidence for a protective effect of ACE inhibitors and angiotensin receptor blockers in patients with COVID-19 was shown in recent work co-authored by one of us - Dr. Loomba.

No evidence exists to suggest prophylactic use of these drugs we do not advise readers to take these drugs in the hopes that they will prevent COVID-19. We wish to emphasize that patients should only take these drugs as instructed by their health care provider.

New clinical trial tests ACE inhibitor against SARS-CoV-2

In collaboration with a multidisciplinary group of investigators, Dr. Loomba has initiated a multicenter (randomized, double-blinded, placebo-controlled) clinical trial to examine the efficacy of ramipril - an ACE inhibitor - compared to a placebo in reducing mortality, ICU admission or need for mechanical ventilation in patients with COVID-19.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Krishna Sriram is a postdoctoral fellow at the University of California San Diego.

Paul Insel is a professor of pharmacology and medicine at the University of California, San Diego.

Rohit Loomba is a professor of medicine at the University of California, San Diego.


Introduction

Ever since the outbreak of Corona Virus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been reported to affect more than 21 million individuals and claimed over 7.5 lakhs lives in more than 200 countries around the globe (COVID-19 situation report-209). Although the mortality rate of COVID-19 is low, patients with diabetes mellitus (DM) and hypertension have shown more severe disease and increased fatality [1, 2]. One of the initial studies done in Wuhan before 2 January, 2020, reported that out of 41 patients infected and identified with COVID-19, 8 were diabetes patients (20%), 6 were hypertensive (15%) and 6 had cardiovascular diseases (15%) [3]. Another study including 26 deceased COVID-19 infected patients reported that, 53.8% were hypertensive, 42.3% diabetes patients, and 19.2% had coronary heart disease. In addition, these significant comorbidities were related with an expanded danger of mortality [4]. A study done in China comprising of 72,314 cases reported that DM patients show higher mortality rate (7.3%) when compared to other patients [5]. Of all COVID-19 patients who died in Italy, 20.3% were diabetes patients [6]. A cross-sectional survey ( <"type":"clinical-trial","attrs":<"text":"NCT04331574","term_id":"NCT04331574">> NCT04331574) with 1581 COVID-19 patients was performed in Italy, where except hypertension age, diabetes mellitus, chronic kidney disease and chronic obstructive pulmonary disease predicted mortality [7]. It was suggested that sex and gender disparities played a role in COVID-19 vulnerability [8]. Global Health 50/50 demonstrated nearly equal number of cases in men and women, but increased fatality in men [9]. Several factors like male-female differences in immune response to vaccines, increased adverse drug reaction to antiviral treatment, influence the action of drugs and vaccines in COVID-19 patients [8].

Older age, diabetes, hypertension, coronary artery disease and smoking are major risk factors for severe COVID-19, and all these conditions relate with vascular endothelial dysfunction [10]. This effects the vascular equilibrium and causes vasoconstriction, thrombosis and inflammation. Angiopoietin-2, a biomarker for endothelial dysfunction was found significantly increased in critical COVID-19 patients, it suggests COVID-19-associated microvascular dysfunction [8]. The role of endothelial-dysfunction in COVID-19 pathogenesis and its complications should be the focus of future studies.

The role of renin𠄺ngiotensin-system (RAS) has been suggested in the progression of diabetes. Angiotensin-II (Ang-II) prevents elevated insulin secretion from pancreatic islets in hyperglycemic condition by disrupting β-cell function, and Angiotensin-converting enzyme 2 (ACE2) gene therapy reduces this damaging effect of Ang-II and insulin is released accordingly from β-cells during hyperglycemic condition. Furthermore, both Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) control glucose levels by blocking overactive RAS and improve the morphology and function of islets. In spite of large data obtained from studies in animal models, facts on humans are yet not clear. This suggests for future studies on exploring the medications targeting RAS as a potent therapeutic for diabetes and comorbidities. ACE2 was found to be one of the main receptors of both SARS-CoV and SARS-CoV-2. ACE2 receptors are expressed widely on heart, respiratory tract, intestines, kidneys and pancreas [11].

Till date there is no specific vaccine or medication against COVID-19 [12] and clinicians are using two classes of medications one which acts directly on coronavirus (CoV) and the other that targets human immune system [13]. The most effective therapeutics could be targeting the interaction of host-cell receptor and the virus itself, which will stop the binding of SARS-CoV-2 with ACE2 receptor and ultimately terminate the entry of the virus into the host cell [14]. This approach may enhance diabetes complications, cardiovascular diseases and other comorbidities by affecting normal functioning of ACE2, which ultimately increases Ang-II levels and leads to inflammation and oxidative stress in islets.

Results of some studies have suggested that boosting passive immunity could be an effective approach for the treatment of severe COVID-19. The trials of a recombinant adeno vaccine (AZD1222), developed by Oxford University’s Jenner Institute have begun last month and if data from the trial show positive results, late-stage trials would begin in a number of countries. After vaccination, the spike proteins are produced, which prepares the immune system to attack COVID-19 if it infects body in future.

Apart from these approaches there could be some other strategies that could prove to be potent therapeutics for COVID-19 in context of ACE2. On the other hand, there is a huge controversy regarding the use of ARBs and ACEi medications, as they can increase ACE2 levels and thus make subjects more susceptible to SARS-CoV infection. The present knowledge lacks any clinical data to support the hypothesis that use of ARBs/ACEi increases patients’ susceptibility to COVID-19 infection and suggests both benefit as well as harm. Therefore, it’s better to continue ARBs and ACEi medications until some strong evidence claims such hypothesis to be true.

Exactly how DM and cardiovascular comorbidities are related with increased complications and significantly increased death rates for patients infected with COVID-19 is not known. As COVID-19 is profoundly transmissible and extremely pathogenic, understanding these mechanisms can help in the development of potential and successful treatments for diabetes patients susceptible to COVID-19 infection. In this review we have discussed the role of ACE2 in diabetes and in COVID-19 and analysed the data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.


Abstract

At the time of writing this commentary (February 2020), the coronavirus COVID-19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS-CoV-2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.

At the time of writing this commentary (February 2020), the death toll from the COVID-19 epidemic caused by coronavirus SARS-CoV-2, which emerged in late December 2019 in Wuhan, China (World Health Organization, 2019), has surpassed the combined death toll of the SARS (Severe Acute Respiratory Syndrome) epidemic of 2002–2003 and the MERS (Middle East Respiratory Syndrome) epidemic of 2013 combined (Mahase, 2020). This epidemic seems to be spreading at an exponential rate, with a doubling period of 1.8 days, and there are fears that it might progress to pandemic scales (Cheng & Shan, 2020 ). Yet, no SARS-CoV-2 therapeutics are presently available, albeit some treatment options which await validation have been published, including several broad spectrum antivirals such as favipiravir and remdesivir (Beigel et al., 2019 , Li & De Clercq, 2020 ), the anti-malaria drug chloroquine (Gao, Tian, & Yang, 2020 ), and a traditional Chinese herbal formula (Luo et al., 2020 ). The ultimate solution is, obviously, developing a SARS-CoV-2 vaccine (Patel et al., 2020 Zhang & Liu, 2020 ). However, vaccines for the SARS-CoV developed since its outbreak 18 years ago have not materialized to an approved product. This topic has been reviewed in detail (de Wit, van Doremalen, Falzarano, & Munster, 2016 ) and is beyond the scope of this brief commentary. In addition, there have been concerns about vaccine-mediated enhancement of disease, for example, due to pulmonary immunopathology upon challenge with SARS-CoV (Tseng et al., 2012 ). Moreover, even once a vaccine is approved for human use, high virus mutation rates mean that new vaccines may need to be developed for each outbreak, similarly to the situation with new annual influenza vaccines (Belongia et al., 2017 ). Below, I describe an alternative option which, if proven to be effective, would allow a rapid application in the clinic.

A recent hypothesis suggested that angiotensin receptor 1 (AT1R) inhibitors might be beneficial for patients infected by COVID-19 who experience pneumonia (Sun, Yang, Sun, & Su, 2020 ). This article, however, is only available in Chinese with an English abstract that does not describe its logic besides the notion that the renin–angiotensin system is dysregulated by SARS-CoV-2. A similar suggestion proposing the treatment of COVID-19 patients with AT1R blockers was put forward in a “rapid online response” posted online by the British Medical Journal on February 4, 2020 (Phadke & Saunik, 2020 ). These tentative suggestions were based on the observation that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor binding domain for its spike protein (Lu et al., 2020 Wan, Shang, Graham, Baric, & Li, 2020 ), similarly to the coronavirus strain implicated in the 2002–2003 SARS epidemic (Dimitrov, 2003 Ge et al., 2013 Li et al., 2003 Prabakaran et al 2004 Turner, Hiscox, & Hooper, 2004 ). Moreover, the receptor binding domains of these two coronaviruses share 72% amino acid sequence identity, and molecular simulation has indicated similar ternary structures (Chen, Guo, Pan, & Zhao, 2020 ). However, SARS-CoV-2 includes a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV, and molecular modeling indicated that the receptor binding domain of SARS-CoV-2 has higher affinity for ACE2 compared with SARS-CoV (Chen et al., 2020 ).

Notably, angiotensin-converting enzyme (ACE) and its close homologue ACE2, while both belonging to the ACE family of dipeptidyl carboxydipeptidases, serve two opposing physiological functions. ACE cleaves angiotensin I to generate angiotensin II, the peptide which binds to and activates AT1R to constrict blood vessels, thereby elevating blood pressure. By contract, ACE2 inactivates angiotensin II while generating angiotensin 1–7, a heptapeptide having a potent vasodilator function via activation of its Mas receptor (Santos et al., 2003 ), and thus serving as a negative regulator of the renin–angiotensin system. These opposing actions of ACE and ACE2 were recently reviewed by Smyth, Cañadas-Garre, Cappa, Maxwell, & McKnight, 2019 .

The AT1R antagonists losartan and olmesartan, commonly applied for reducing blood pressure in hypertensive patients, were shown to increase cardiac ACE2 expression about three-fold following chronic treatment (28 days) after myocardial infarction induced by coronary artery ligation of rats (Ishiyama et al., 2004 ). Losartan was also shown to upregulate renal ACE2 expression in chronically treated rats (Klimas et al., 2015 ). In agreement with these observations, higher urinary ACE2 levels were observed in hypertensive patients treated with the AT1R antagonist olmesartan (Furuhashi et al., 2015 ). Taken together, these observations suggest that chronic AT1R blockade results in ACE2 upregulation in both rats and humans.

As described above, ACE2 is the common binding site for both the SARS-CoV of the 2002–2003 SARS epidemic and, most likely, also the SARS-CoV-2 strain underlying the current COVID-19 epidemic. Hence, the suggestion to treat SARS patients with AT1R antagonists for increasing their ACE2 expression seems counter-intuitive. However, several observations from studies on SARS-CoV, which very likely are relevant also for SARS-CoV-2, seem to suggest otherwise. It has been demonstrated that the binding of the coronavirus spike protein to ACE2, its cellular binding site, leads to ACE2 downregulation, which in turn results in excessive production of angiotensin by the related enzyme ACE, while less ACE2 is capable of converting it to the vasodilator heptapeptide angiotensin 1–7. This in turn contributes to lung injury, as angiotensin-stimulated AT1R results in increased pulmonary vascular permeability, thereby mediating increased lung pathology (Imai et al., 2005 Kuba et al., 2005 ). Therefore, higher ACE2 expression following chronically medicating SARS-CoV-2 infected patients with AT1R blockers, while seemingly paradoxical, may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin-mediated AT1R activation caused by the viral infection, as well as upregulating ACE2, thereby reducing angiotensin production by ACE and increasing the production of the vasodilator angiotensin 1–7. These aspects on the role of dysregulated ACE2 in SARS-CoV pathogenesis are reviewed in detail by de Wit et al., 2016 . Incidentally, following the SARS-CoV epidemic of 2002–2003, ACE2 inhibitors were suggested as SARS therapeutics (Huentelman et al., 2004 Turner et al., 2004 ) however, this proposal has not led to new drugs.

Incidentally, in the context of the human immunodeficiency viruses (HIV), it has been demonstrated that higher expression levels of the HIV binding sites CCR5 and CD4 protect from, rather than increase, HIV virulence. Michel et al. reported that HIV employs its early gene Nef product for avoiding superinfection during the viral-entry step by downregulating CCR5. This Nef-mediated downregulation enhances the endocytosis rate of both CCR5 and CD4, which in turn facilitates efficient replication and spread of HIV, thereby promoting AIDS pathogenesis (Michel, Allespach, Venzke, Fackfmicheller, & Keppler, 2005 ). It remains to be studied if a comparable mechanism for avoiding superinfection has evolved in coronaviruses in which case, the suggestion of applying AT1R blockers as SARS therapeutics, even that they upregulate the expression of the ACE2 virus binding site, will not seem paradoxical.

Losartan, telmisartan, olmesartan (and additional AT1R antagonists) are widely applied in the clinic since the 1990s for control of hypertension and kidney disorders, and are known as safe drugs that are rarely implicated in adverse drugs events (Deppe, Böger, Weiss, & Benndorf, 2010 McIntyre, Caffe, Michalak, & Reid, 1997 ). However, it should be noted that around half of SARS-CoV patients developed hypotension during their hospitalization (Yu et al., 2006 ). At time of writing this commentary, no comprehensive information is available on hypotension rates among hospitalized SARS-CoV-2 patients it is thus premature to estimate what percentage of SARS patients of the currently ongoing epidemic can be safely treated with AT1R blockers without risking exacerbated hypotension.

The tentative suggestion to apply AT1R antagonists such as losartan and telmisartan as SARS-CoV-2 therapeutics for treating patients prior to the development of acute respiratory syndrome remains unproven until tried. At time of writing this brief commentary, the end of the COVID-19 epidemic is not in sight and drastic actions are required (and being done) for containing its spread and death toll. Hence, the most rapid approach for assessing its feasibility is to analyze clinical patient records and apply datamining technologies to determine whether patients who were prescribed with AT1R antagonists prior to their diagnosis (for treating their hypertension, diabetic kidney disease, or other indications) had better disease outcome. Moreover, the percentage of people chronically medicated with AT1R blockers in the general population should be compared with the percentage among hospital admissions of SARS-CoV-2 infected patients presenting serious symptoms. If the latter percentage would be found to be significantly smaller, this would support the notion that AT1R antagonists confer protection from severe symptoms among SARS-CoV-2 infected individuals. Knowledge gained for such datamining of clinical records seems crucial for reducing the mortality and morbidity of SARS-CoV-2. At the same time, efforts must be made for developing a SARS-CoV-2 vaccine.


2 METHODS

2.1 Data sources and search strategy

A systematic literature search was conducted to identify studies investigating the association between ACEIs or ARBs and pneumonia or COVID-19 in PubMed, Embase (searches using OVID), The Cochrane Central Register of Controlled Trials (CENTRAL), and Clinical trial.gov. The last search was updated on 7 September 2020. The following MeSH terms were used: “angiotensin-converting enzyme inhibitors” or “angiotensin receptor antagonists” or “mineralocorticoid receptor antagonists” and “pneumonia”. The key words used for the search strategy are listed in the supplementary materials. The references cited in the retrieved studies were hand-searched for the collection of missing relevant studies.

2.2 Study selection and quality assessment

Two reviewers independently screened titles and abstracts, and further assessed the full text of each potentially relevant study to determine eligibility for inclusion. Reviews, congress reports, case reports, animal experiments and publications in languages other than English were excluded.

We considered the incidence of pneumonia in all adult patients, irrespective of risk factors at baseline, as the primary outcome. Every case of pneumonia considered in our investigation was either a new case, a recurrent case or a hospital-acquired pneumonia. Diagnosis of pneumonia was based on clinical, radiological or microbiological criteria, or International Classification of Disease codes. We did not consider undefined data or data on upper respiratory tract infections or radiation pneumonitis. The secondary outcome was pneumonia-related mortality, including fatal pneumonia or in-hospital death or 30-day mortality. All of these secondary outcomes had to be caused primarily by pneumonia rather than other co-existing comorbid conditions. 3 All relevant clinical studies (randomized–controlled trials [RCTs], cohort studies, case–control studies and nested case–control studies, as well as case-crossover studies) with ACEIs or ARBs as interventions and with an incidence of pneumonia were considered.

The diagnosis of COVID-19 must be proven by detection of SARS-CoV-2 RNA in the patient's upper or lower respiratory tract system. Treatment with RAAS blocking agents was defined as treatment with either an ACEI or an ARB or both (just 3 patients in 1 study). COVID-19 related adverse severe clinical outcomes are defined as admission to the intensive care unit, the use of assisted ventilation or death. However, we only include peer-reviewed articles considering the current situation, some observation studies are online available without careful peer review, and thus the quality might raise concerns.

To avoid considering duplicated published data, we excluded the earlier publications conducted in the same study cohort and only considered the latest publications. In our investigation, the treatment group was defined as being treated with any kind of ARBs or any kind of ACEIs. The control group was defined as being treated with a placebo or any other cardiovascular drug such as calcium-channel blockers or β-blockers. Cohort studies had to follow patients to determine pneumonia outcomes. In case–control studies, cases had to be patients with a diagnosis of pneumonia. Controls should be randomly selected to match the cases. A nested case–control study is a variation of a case–control study in which cases and controls are drawn from the population in a fully predefined cohort. In a case–crossover study, as described, 4 the study population consists of subjects who have experienced an episode of pneumonia. Similar to a crossover trial, each study subject serves as their own control.

The methodological quality of RCTs was evaluated using the Cochrane Collaboration's tool for RCTS with the following parameters: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, selective reporting. The quality of included cohort and case control studies was assessed using the Newcastle–Ottawa scale, which has 3 aspects including 8 criteria and yield scores ranging from 0 (high risk of bias) to 9 (low risk of bias). Studies with Newcastle–Ottawa scale scores <6/9 (considered moderate-to-high risk of bias) were excluded (Table S1).

Overall quality of evidence was evaluated using the Grading of Recommendations, Assessment, and Evaluation (GRADE) framework. 5

2.3 Data extraction and analysis

Two independent authors extracted the following data from full-text articles: study design and size, location, population characteristics, primary outcomes, data of relevant outcomes. Data were obtained irrespective of whether they had been reported as predefined outcomes or as adverse effects. We chose the odds ratio (OR) as the measurement estimate for effect because relative estimates are better comparable than absolute effects across studies with different designs, populations, and lengths of follow-up as described previously. 6 We aimed to extract the maximally adjusted OR that included the greatest number of covariates from the original publication for predescribed outcomes. Otherwise, we used the raw data to convert to crude OR through classic methods, or Peto's method if 1 arm had a zero-count cell. 7 We used the hazard ratio (HR) when OR was not available nor possible to calculate. To explore differences in estimates for outcomes, we presented the results stratified according to study design. Considering the potential risk of bias, subgroup analysis in which compare results from the adjusted and unadjusted studies was also conducted. Studies that met the inclusion criteria but could not be pooled due to insufficient data were summarized qualitatively. Either fixed-effects model or, in the presence of heterogeneity, the random-effects method was used in the pooled results. Data were expressed as OR and 95% confidence intervals (95% CIs). Heterogeneity across studies was assessed by testing with the I 2 -statistic, considering 25%, 50% and 75% as an indication of low, moderate, and high variability, respectively. 8

Funnel-plot analysis and Begg test were performed to evaluate potential publication bias. All analyses were performed using Stata/SE version 14.0 (StataCorp LP, College Station, Texas, USA) and RevMan version5.3.5 (Nordic Cochrane Centre, Cochrane Collaboration, 2014). Tests were 2-sided, and a P-value <.05 was considered statistically significant.


3 RESULTS

3.1 Literature retrieval

Through the literature search, we retrieved 3204 articles. In total, 1448 articles were screened after duplicates were removed. After the titles and abstracts were read, 1233 articles were excluded. Among the remaining 215 papers, 25 articles were included in our study after the full texts were reviewed (Figure 1).

3.2 Study description

A total of 22,734 participants were enrolled in the 25 included studies. The study sample size ranged from 36 to 7933 participants, with a mean age ranging from 52 to 78 years. Most studies included participants with hypertension, and 10 studies included the general population. Most of the studies were carried out in China (n = 11) and the United States (n = 4), and other studies were conducted in Italy, the UK, Spain, France, South Korea, and Turkey 11-35 (Tables 1–2).

Author Country Journal Study design Sample size Male Age (years)
ACEI/ARB Non-ACEI/ARB ACEI/ARB Non-ACEI/ARB ACEI/ARB Non-ACEI/ARB
Mean SD Mean SD NOS
Bean, D M UK European Journal of Heart Failure A retrospective cohort study 399 801 231 455 73.02 13.46 65.45 18.1 8
Bae, D J USA The American Journal of Cardiology A propensity score-matched analysis 78 71 47 36 65 14.81 64 19.26 7
Senkal, N Turkey Anatolian Journal of Cardiology A propensity score-matched analysis 104 52 53 30 63 11.98 65 12 7
Khera, R (Outpatient Study) USA medRxiv: the preprint server for health sciences A propensity score-matched analysis (outpatient Study) 1453 810 796 331 68.50 13.35 71.0 14.81 8
Khera, R (Inpatient Study) USA medRxiv: the preprint server for health sciences A propensity score-matched analysis (inpatient Study) 4587 3346 2170 1431 76 11.11 78.0 11.85 8
Gao, C China European Heart Journal A retrospective cohort study 183 527 104 266 62.64 11 64.84 11.19 8
Zhang, P China Circulation Research A propensity score-matched analysis 174 348 94 197 64 8.89 64 9.63 8
Li, J China JAMA Cardiology A single-center retrospective cohort study 115 247 68 121 65.0 11.85 67.0 11.11 5
Jung, S Y Korea Clinical Infectious Diseases A nationwide population-based cohort study 377 1577 8
Priyank, S USA Journal of Hypertension A retrospective cohort study 207 324 87 131 64.0 12.4 57.6 17.8 7
Zhou, X China Clinical and Experimental Hypertension A single-center retrospective cohort study 15 21 9 10 58.5 10.1 69.2 7.5 6
Pan, W China Hypertension (Dallas, Tex.: 1979) A single-center retrospective cohort study 41 241 16 127 70 9.63 69 10.37 6
Lam, K W USA The Journal of Infectious Diseases A single-center retrospective cohort study 335 279 189 149 68 15.56 73 15.56 7
Yang, G China Hypertension (Dallas, Tex.: 1979) A single-center retrospective cohort study 43 83 21 41 65 11.11 67 9.63 7
Zeng, Z H China medRxiv A single-center retrospective cohort study 28 47 12 23 64 12 69 10 6
Selcuk, M Turkey Clinical and Experimental Hypertension A retrospective cohort study 74 39 36 23 67 11 58 10 5
Chen, C China Journal of the American Heart Association A single-center retrospective cohort study 355 827 176 404 68 11.85 68 10.37 7
Huang, Z China Annals of Translational Medicine A retrospective cohort study 20 30 10 17 52.65 13.12 67.77 12.84 5
Feng, Z China medRxiv A multicenter, retrospective cohort study 16 49 10 23 57 10.37 63 11.85 8
Felice, C Italy American Journal of Hypertension A single-center retrospective cohort study 82 51 59 27 71 12.60 76.2 11.9 7
Wang, Z C China Medical Science Monitor A propensity score-matched analysis 62 62 33 30 68.5 12.68 67 10.74 7
Yahyavi, A Iran Internal and Emergency Medicine A retrospective cohort study 500 2053 272 1226 66.8 12.3 55.9 18.4 6
Covino, M Italy Internal Medicine Journal A retrospective cohort study 111 55 78 31 72 11.11 77 12.59 5
Palazzuoli, A Italy Journal of the American Heart Association A multicenter, retrospective cohort study 304 477 193 305 72.4 10.4 66 14.8 5
Negreira-Caamano, M Spain High Blood Pressure & Cardiovascular Prevention A single-center retrospective cohort study 392 153 206 77 75.9 12.1 78 12.9 6
Lafaurie, M France Fundamental & Clinical Pharmacology A retrospective cohort study 73 36 39 20 73 12.59 77 13.33 5
  • Abbreviations: ACEI, angiotensin-converting enzyme inhibitor ARB, angiotensin receptor blocker NOS, Newcastle Ottawa Scale.
Author Diagnosis of COVID-19 Data sources Study population Follow-up time Adjustment factors
Bean, D M Real-time RT-PCR Extracted from clinical notes, outpatient clinic letters and inpatient medication orders General population 21 days Age, sex, hypertension, diabetes mellitus, chronic kidney disease, ischemic heart disease, heart failure
Bae, D J RT-PCR of a nasopharyngeal swab or a bronchoalveolar lavage Extracted from the electronic medical record and the index healthcare COVID-19 contact (a patient's first interaction with a healthcare system to discuss COVID-19 symptoms and testing via phone call, telemedicine visit, outpatient clinic visit, or emergency room visit was defined as the index healthcare COVID-19 contact) General population Age, hypertension, dyslipidemia, diabetes/pre-diabetes, CAD, CHF, CVA, chronic lung disease, and CKD/ESRD
Senkal, N RT-PCR of a nasopharyngeal swab and an ultra low-dose spiral CT of the chest Extracted from patient charts General population Age, sex, sick days before hospital admission, comorbidities (diabetes mellitus, COPD/asthma, CAD, CHF, and CKD), current smoking status, number of antihypertensives used, furosemide use, doxazosin use, and serum creatinine level)
Khera, R (Outpatient Study) NA A research database from a single large US health insurance provider People with hypertension Age, gender, race, insurance type, conditions, diabetes, myocardial infarction, heart failure and chronic kidney disease, each of the comorbidities in the Charlson Comorbidity Index, and the number of antihypertensive agents used for the patient
Khera, R (Inpatient Study) NA A research database from a single large US health insurance provider People with hypertension Age, gender, race, insurance type, conditions, diabetes, myocardial infarction, heart failure and chronic kidney disease, each of the comorbidities in the Charlson Comorbidity Index, and the number of anti-hypertensive agents used for the patient
Gao, C According to WHO interim guidance and diagnosis and treatment protocol for novel coronavirus pneumonia from the National Health Commission of China Extracted from electronic medical records General population The final date of follow-up was 1 April 2020 and the median duration of follow-up (hospitalization) was 21 (12– 32) days.
Zhang, P CT manifestations and RT-PCR according to the New Coronavirus Pneumonia Prevention and Control Program (5th edition) Extracted from the electronic medical system, picture achieving and communication system, laboratory information system, medical history and doctor advices People with hypertension The final date of follow-up was March 7, 2020 Imbalanced variables (D-dimer, procalcitonin, and unilateral lesion) and in-hospital medications (antiviral drug and lipid-lowering drug) between ACEI/ARB versus non-ACEI/ARB groups in following mixed-effect Cox model
Li, J RT-PCR Extracted from electronic medical records General population
Jung, S Y RT-PCR of a nasopharyngeal swab The Korean Health Insurance Review and Assessment database General population All patients were followed until the first instance of death or 8 April 2020. Age, sex, Charlson comorbidity index, immunosuppression, and hospital type
Priyank, S RT-PCR of a nasopharyngeal swab Extracted from electronic medical records General population Age, sex, BMI, baseline comorbidities, and presenting illness severity
Zhou, X According to the COVID19 diagnosis and treatment program issued by the Chinese National Health Committee Extracted from electronic medical records People with hypertension Age, sex, hospitalization time, time from onset to hospital admission
Pan, W According to the Diagnosis and Treatment of Novel Coronavirus Pneumonia (sixth edition) guidelines published by the National Health Commission of China Extracted from electronic medical records People with hypertension The clinical outcomes were recorded until February 24, 2020.
Lam, K W RT-PCR of a nasopharyngeal swab Extracted from electronic medical records People with hypertension Age, gender, history of heart failure, chronic obstructive pulmonary disease, and asthma (comorbidities that were significantly different between groups)
Yang, G According to the guideline of SARS-CoV-2 (The Fifth Trial V ersion of the Chinese National Health Commission) Extracted from electronic medical records People with hypertension The clinical outcomes were monitored up to March 3, 2020, the final date of follow-up.
Zeng, Z H According to the criteria previously established by the WHO Extracted from clinical and laboratory records People with hypertension Follow-up was cutoff on March 8, 2020.
Selcuk, M RT-PCR Extracted from electronic medical records People with hypertension Age, D-dimer, LDH
Chen, C According to symptoms, RT-PCR of a nasopharyngeal swab and radiological findings of interstitial pneumonia on CT scan Extracted from patients' electronic medical records People with hypertension The clinical follow-up was terminated on April 24, 2020, when the last COVID-19 patient was discharged.
Huang, Z According to the Novel Coronavirus Pneumonia Diagnosis and Treatment Guideline (5th ed.) (in Chinese) published by the National Health Commission of China Extracted from electronic nursing and medical records People with hypertension
Feng, Z RT-PCR of nasal and pharyngeal swab specimens Extracted from electronic medical records People with hypertension The final date of follow-up was March 15, 2020. Age
Felice, C RT-PCR of a nasopharyngeal swab Patients' demographics and clinical characteristics were collected by medical records and entered into an anonymous database People with hypertension Age, gender, body mass index, days with symptoms before admission, previous cardiovascular events, diabetes, and cancer
Wang, Z C RT-PCR of a nasopharyngeal swab Extracted from electronic medical records People with hypertension Age, sex, BMI, previous comorbidities, vital signs, disease severity, ion concentration, hepatic and renal function, blood cell count, CRP, and IL-6 on the clinical outcomes
Yahyavi, A Patients diagnosed with COVID-19 according to World Health Organization interim guidance The data were collected from the SEPAS system, a national integrated care electronic health record system General population Patients were followed after discharge for at least 120 days.
Covino, M According to the WHO interim guidance Extracted from electronic medical records People with hypertension
Palazzuoli, A RT-PCR of a nasopharyngeal swab Extracted from electronic medical records General population
Negreira-Caamano, M NA Extracted from electronic medical records People with hypertension The follow-up period was measured in days from hospital admission to the date of the clinical event or to hospital discharge if no events were registered.
Lafaurie, M According to the WHO guidance Extracted from electronic medical records General population
  • Abbreviations: CT, computed tomography RT-PCR, reverse transcriptase polymerase chain reaction WHO, World Health Organization.

3.3 Meta-analysis

3.3.1 ACEI/ARB use and the risk of mortality in COVID-19 patients

The overall analysis of mortality included 21 studies. The association between ACEI/ARB use and the risk of mortality was estimated. Overall, the risk of mortality was significantly lower in COVID-19 patients taking ACEIs/ARBs than in those not taking ACEIs/ARBs (OR = 0.65 95% CI: 0.46, 0.85 Figure 2). However, there was substantial heterogeneity among the studies (I 2 = 73.37%, p < .05). A subgroup analysis was performed based on whether the participants had hypertension. In the general population, the risk of mortality in patients taking ACEIs/ARBs was similar to that in patients not taking ACEIs/ARBs (OR = 0.98 95% CI: 0.75, 1.22 I 2 = 13.62% Figure 2). In the studies performed with patients with hypertension, the risk of mortality was significantly lower in patients taking ACEIs/ARBs than in those not taking ACEIs/ARBs (OR = 0.51 95% CI: 0.29, 0.73 I 2 = 73.37% Figure 2). No significant publication bias was observed (p value of the Egger's test = 0.65, Table 3). Meta-regression analysis showed that asthma (p = .00) and cerebral vascular diseases (p = .00) have significant modulating effect of ACEIs/ARBs treatment on the mortality of COVID-19 patients (Table 4). A single study was used to analyze the source of heterogeneity. However, no study is considered a source of heterogeneity (Appendix Figure A1).

Subgroup analysis OR/SMD 95% CI I 2 (%) p (the χ 2 test) p (the Egger's test) p (test of group differences)
Mortality 0.65 0.46, 0.85 73.37 .00 .65
General population 0.98 0.75, 1.22 13.62 .00
People with hypertension 0.51 0.29, 0.73 73.37 .00
Severe disease 0.89 0.63, 1.15 38.55 .13 .72
Severity/mortality 0.69 0.43, 0.95 22.90 .24 .59
Hospitalization 0.79 0.60, 0.98 0.00 .65 .96
ICU* * ICU: transfer to the intensive care unit.
0.96 0.56, 1.37 88.31 .00 .07
General population 1.14 0.57, 1.71 89.73 .01
People with hypertension 0.36 0.19, 0.53 0.00 .01
Mechanical ventilation 0.89 0.61, 1.16 3.19 .35 .11
ARDS 0.71 0.46, 0.95 0.00 .54 .90
Dialysis 1.24 0.09, 2.39 0.00 .83 .97
Length of hospital stay 0.05 -0.16, 0.26 84.43 .00 .01
General population 0.10 -0.32, 0.53 93.24 .74
People with hypertension 0.02 -0.17, 0.21 44.20 .74
  • Abbreviations: ARDS, acute respiratory distress syndrome ICU, intensive care unit OD, odds ration.
  • * ICU: transfer to the intensive care unit.
Age Male Diabetes Coronary heart disease Heart failure Chronic lung disease COPD Asthma Cerebral vascular diseases Chronic liver diseases Chronic kidney disease Malignancy
Mortality 0.72 0.53 1.00 0.64 0.43 0.72 0.15 0.00 0.00 0.70 0.09 0.47
Severe disease 0.29 0.25 0.41 0.48 0.48 0.08 0.99 0.38 0.92 0.64 0.79 0.83
ICU 0.01 0.18 0.21 0.81 0.63 0.63 0.55 0.72 0.34 0.18 0.32 0.01
Length of hospital stay 0.06 0.63 0.35 1.00 0.53 0.48 0.01 0.20 0.46 0.57

3.3.2 Effect of ACEI/ARB use on COVID-19 severity

The overall assessment with the random-effects model showed that the use of ACEIs/ARBs was not associated with an elevated risk of severe COVID-19 (OR = 0.89 95% CI: 0.63, 1.15 I 2 = 38.55%), mechanical ventilation (OR = 0.89 95% CI: 0.61, 1.16 I 2 = 3.19%), transfer to the ICU (OR = 0.96 95% CI: 0.56, 1.37 I 2 = 88.31% Figure 3) or dialysis (OR = 1.24 95% CI: 0.09, 2.39 I 2 = 0.00%). Except for the analysis of transfer to the ICU, the other analyses had acceptable degrees of heterogeneity. The effect estimates showed an overall protective effect of the use of ACEIs/ARBs against severity/mortality (OR = 0.69 95% CI: 0.43, 0.95 I 2 = 22.90%) and ARDS (OR = 0.71 95% CI: 0.46, 0.95 I 2 = 0.00%), and all the analyses had acceptable degrees of heterogeneity (Table 3). In the analysis of the risk of transfer to the ICU, significant differences were observed between subgroups. In the studies involving people with hypertension, there was a significantly lower risk of transfer to the ICU in those taking ACEIs/ARBs than in those not taking ACEIs/ARBs (OR = 0.36 95% CI: 0.19, 0.53 I 2 = 0.00% Figure 3 and Table 3). Meta-regression analysis showed that age (p = .01) and malignancy (p = .01) has a significant modulating effect of ACEIs/ARBs treatment on the risk of transfer to the ICU of COVID-19 patients (Table 4). Furthermore, meta-regression analysis showed that all the modulators have no significant modulating effect of ACEIs/ARBs treatment on the severity of COVID-19 patients (p > .05, Table 4).

3.3.3 Effect of ACEI/ARB use on the risk of hospitalization and length of hospital stay in COVID-19 patients

The effect estimates showed an overall protective effect of the use of ACEIs/ARBs against hospitalization (OR = 0.79 95% CI: 0.60, 0.98 I 2 = 0.00%), with acceptable degrees of heterogeneity. The pooled analysis showed that the length of hospital stay (SMD = 0.05 95% CI: −0.16, 0.26 I 2 = 84.43%) in COVID-19 patients were not affected by the use of ACEIs/ARBs, although there was heterogeneity among the studies. No significant differences between subgroups were observed (Table 3). However, the analysis had a significant publication bias (Appendix Figure A2). Meta-regression analysis showed that chronic obstructive pulmonary disease (COPD) has a significant modulating effect of ACEIs/ARBs treatment on the length of hospital stay of COVID-19 patients (p = .01, Table 4).


Angiotensin receptor blockers/antagonists and cancer: a closer look at potential mechanisms

An important aspect to discuss, therefore, is whether there is sufficient biological plausibility to support the hypothesis that ARBs favour cancer development, and whether the postulated mechanism advocated by Sipahi et al. 17 in their discussion has any solid basis. This mechanism proposes that the rise in angiotensin (Ang) II during ARB treatment will activate the non-blocked AT2 receptors, thereby inducing tumour angiogenesis.

Indeed, several tumoural cell types have been reported to express Ang II receptors. 23 These include melanoma, brain, lung, pancreatic, renal, breast, ovarian, bladder, and prostate cancer. Moreover, in high-grade astrocytomas, tumour Ang II receptor expression was associated with a high grade of malignancy, increased cellular proliferation, and angiogenesis, and thus predicted poor prognosis. 24

As demonstrated in the Matrigel model in mice, Ang II induces angiogenesis via activation of the vascular endothelial growth factor (VEGF)/endothelial NO synthase (eNOS) pathway. 25 This involves AT1 rather than AT2 receptors, since only ARBs blocked this process. 25 In line with this observation, ACE-I, 26 ARBs, 27 and a recombinant antibody (R6313/G2) against the AT1 receptor 28 displayed antineoplastic activity and inhibited angiogenesis in various tumoural experimental models.

With regard to the potential significance of the stimulation of unopposed AT2 receptors in patients treated with ARBs, the role of the AT2 receptor in cancer is controversial. This may depend on the experimental model and the cancer type. In the model of subcutaneously transplanted syngeneic xenografts pancreatic ductal carcinoma cells, tumour growth was more rapid and the tumour vasculature was significantly enhanced in AT2 receptor knock-out mice than in wild-type animals. 29 In addition, the growth of pancreatic ductal carcinoma cells in vitro was decreased when cultured with AT2 receptor gene transfected fibroblasts. 29 Furthermore, overexpression of AT2 receptor induced cell death in lung adenocarcinoma cells via activation of apoptosis. 30 Taken together, these data suggest that AT2 receptors stimulation results in an antitumour effect. This may be due to the fact that AT2 receptors exert anti-angiogenic effects by interfering with VEGF/eNOS-mediated endothelial cell migration and tube formation. 31 Yet, AT2 receptor gene deficiency attenuated susceptibility to tobacco-specific nitrosamine-induced lung tumourigenesis by down-regulating the level of transforming growth factor β, 32 thus supporting a pro-tumour effect of AT2 receptors. A possible explanation for these contradicting observations is that AT2 receptors may achieve an AT1 receptor-like phenotype under pathological conditions, e.g. inducing vasoconstriction/angiogenesis rather than vasodilation/anti-angiogenesis. 33 Finally, studies with the AT2 receptor agonist compound C21 so far have not produced any alert for cancer, although it should be acknowledged that this has been generally involved in short-term studies only.

Angiotensin receptor blockers/antagonists as well as ACE-I increase plasma and tissue concentrations of Ang (1–7). In a human lung tumour xenograft model, athymic mice with tumours treated with Ang-(1–7) by osmotic mini pumps for 28 days had a 30% reduction in tumour volume associated with reduced tumoural cyclooxygenase-2 expression and a decreased vessel density. 34 Angiotensin (1–7) has anti-angiogenic effects in the chick chorioallantoic membrane model and reduces VEGF-A expression in tumours. 35 In vitro, Ang-(1–7) inhibits lung cancer cell growth through the activation of the MAS receptor and this effect cannot be prevented by either AT1 nor AT2 receptor antagonists. 36

Angiotensin receptor blockers/antagonists and ACE-I differently affect the level of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), induced in plasma and tissues. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of pluripotent haematopoietic stem cell proliferation, 37 is formed in vivo by enzymatic cleavage of the N-terminus of thymosin beta4 by prolyl oligopeptidase (POP), and is physiologically degraded by the N-terminal domain of ACE. 37, 38 Its accumulation during ACE inhibition may partially mediate the cardioprotective effect of ACE-inhibitors. However, Ac-SDKP has also been suggested to be pro-angiogenic: Ac-SDKP stimulates endothelial cell proliferation, migration, and tube formation in a dose-dependent manner and increases myocardial capillary density in rat hearts with MI. 39 It also stimulates an angiogenic response in the chicken embryo chorioallantoic membrane, 40 in the abdominal muscle of the rat, and in a model of surgically induced hind-limb ischaemia. 41 N-acetyl-seryl-aspartyl-lysyl-proline levels are increased in haematologic and solid malignancies (breast, colon, head and neck, kidney, lung, skin, ovary, and prostate) and enhanced activity of POP is also detected in cancer tissues. 42 Thus, in theory at least, ARBs (which do not alter Ac-SDKP concentrations) should not stimulate angiogenesis via this pathway, whereas ACE-I could.

Finally, the rise in renin per se, as occurring during any type of RAS blockade, may have detrimental consequences. Indeed, renin as well as its precursor prorenin bind to the (pro)renin receptor [(P)RR] and trigger intracellular signalling in an Ang II-independent manner. Interestingly, the (P)RR has recently been shown to be a component of the Wnt receptor complex and to be essential for the signalling of the canonic Wnt-β-catenin pathway although not necessarily in a (P)RR-dependent manner. 43 Since the Wnt-β-catenin pathway is essential in embryonic and adult stem cell biology and therefore in cancer, one could imagine that the increased levels of renin and prorenin, as occurring during ARB therapy (as well as during any other type of RAS blockade!), are responsible for augmented Wnt-β-catenin signalling and cancer. However, up to now, the role of the (P)RR in the Wnt-β-catenin signalling has only been demonstrated in Xenopus 43 and clearly, more work is needed to substantiate these findings in higher mammals.


What Is the Difference between ARBs and ACE Inhibitors?

Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors differ the most in the way that they affect the renin-angiotensin-aldosterone (RAA) system, which helps to control blood pressure. Other slight differences between ARBs and ACE inhibitors can include a decreased risk of certain side effects, especially persistent cough with ARBs. Some studies have suggested that women who use ARBs after a heart attack have higher survival rates than women who use ACE inhibitors. In most other ways, these two classes of drugs are very similar.
ARBs and ACE inhibitors affect the RAA system in slightly different ways that both relate to angiotensin II. This is a powerful chemical that signals blood vessels to constrict, and it can contribute to hypertension. ARBs, such as candesartan, losartan, and irbesartan, prevent angiotensin II from connecting with receptors on small arteries. This means that the blood vessels don’t narrow, and blood pressure is reduced.
The action of ACE inhibitors is very different, though the overall effect is similar. Medications like benzapril, enalapril, and lisinopril prevent the conversion of angiotensin I into angiotensin II. The absence of this chemical means the blood vessels get few chemical messages to constrict, and blood pressure normalizes.
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Another difference between the two may be the degree to which certain side effects are experienced. Patients who have trouble tolerating ACE inhibitors are often switched to an ARB. This is mainly due to the symptoms of difficult coughing that ACE inhibitors commonly cause. An ARB can have this side effect, too, but not as often, and many patients are made more comfortable if they switch to one.
Moreover, preliminary research suggests that ARBs may be a better choice for women who have experienced a heart attack. Some studies have evaluated mortality rates in women who take these medications after a heart attack. The evidence suggests that ARBs appear to improve life expectancy, but only for women. There needs to be more study in this area to confirm these results.
Despite some differences, ARBs and ACE inhibitors are similar in many ways. They’re both recommended to regulate high blood pressure, lengthen survival after a heart attack, and slow the progression of kidney failure caused by diabetes. Drugs from these classes may additionally protect against stroke. It’s also suggested that these medications may help prevent high cholesterol.
These drugs also have comparable side effects, including headache, dizziness, and cough. Additional adverse reactions include diarrhea, rash, and allergy. Both classes of drugs can cause serious birth defects and may interact with the same medications, like lithium.


Do Angiotensin II Receptor Blockers (ARBs) or other factors control the level of ACE2 expression? [coronavirus receptor] - Biology

SARS-CoV-2 infection induces an imbalance in the renin–angiotensin system.

We present current clinical strategies that attempt to rebalance the RAS in COVID-19 patients.

There is interest in stimulating the protective arm of the RAS in COVID-19 patients.

20-Hydroxyecdysone, a Mas receptor (MasR) activator, has potential for the treatment of COVID-19.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has reached pandemic proportions with negative impacts on global health, the world economy and human society. The clinical picture of COVID-19, and the fact that Angiotensin converting enzyme 2 (ACE2) is a receptor of SARS-CoV-2, suggests that SARS-CoV-2 infection induces an imbalance in the renin–angiotensin system (RAS). We review clinical strategies that are attempting to rebalance the RAS in COVID-19 patients by using ACE inhibitors, angiotensin receptor blockers, or agonists of angiotensin-II receptor type 2 or Mas receptor (MasR). We also propose that the new MasR activator BIO101, a pharmaceutical grade formulation of 20-hydroxyecdysone that has anti-inflammatory, anti-fibrotic and cardioprotective properties, could restore RAS balance and improve the health of COVID-19 patients who have severe pneumonia.


Introduction

Angiotensin II (Ang II) is a powerful vasoconstrictor that induces the secretion of aldosterone and thereby the retention of sodium and water, which increases the circulating fluid volume and maintains normal blood pressure in hypotensive situations. In addition to its role in regulating blood pressure, Ang II has been shown to have important inflammatory and oxidative actions that are associated with atherosclerosis and acute coronary syndromes (Figure 1).

Proinflammatory effects of Ang II and their clinical consequences. 5HT=5-hydroxytryptamine (serotonin) Ang II=angiotensin II AP-1=activator protein-1 AT1 receptor=angiotensin II type 1 receptor BP=blood pressure CD40L=CD40 ligand eNOS=endothelial nitric oxide synthase IκB=inhibitor κB MCP-1=monocyte chemoattractant protein-1 MMPs=matrix metalloproteinases NADPH=the reduced form of nicotinamide-adenine dinucleotide phosphate NFκB=nuclear factor κB NO=nitric oxide PAI-1=plasminogen activator inhibitor-1 PI-3K=phosphatidylinositol 3-kinase ROS=reactive oxygen species TF=tissue factor TNF-α=tumour necrosis factor-α TXA2=thromboxane A2.

Ang II is generated in the circulation (plasma) and in tissue – particularly the arterial wall. Endothelial cells are the major source of angiotensin-converting enzyme (ACE), which converts angiotensin I into Ang II. As Ang II is rapidly destroyed by angiotensinases (half-life of approximately 1 min), local renin–angiotensin systems probably play an important role in vascular-wall pathophysiology.

The two major classes of Ang II receptors are the type 1 (AT1) and type 2 (AT2) receptors. AT2 receptors are not abundant in healthy adults however, this class is upregulated in stressful conditions including vascular injury, myocardial infarction and heart failure. 1 The actions of Ang II mediated through AT1 receptors – such as vasoconstriction and inflammation – oppose those mediated through AT2 receptors, which include the release of nitric oxide (NO), an anti-inflammatory vasodilator that also reduces platelet aggregation and may facilitate the action of insulin. 2, 3, 4, 5, 6, 7, 8, 9 When AT1 receptors are inactive or blocked, the actions mediated by AT2 receptors are likely to dominate. 3 Thus, blockade of the renin–angiotensin system by angiotensin II receptor blockers (ARBs) may have dual effects: a decrease in vasoconstriction and aldosterone secretion accompanied by vasodilation mediated by an increase in NO.


Enhancing Healthcare Team Outcomes

ACE inhibitors are one of the most widely used drugs for hypertension and heart failure, but their popularity does not mean they do not need the management of an interprofessional team. Besides the nephrologists and cardiologists, these drugs are widely prescribed by nurse practitioners and primary care providers. While ACE inhibitors are relatively safe, a pharmacist should examine the patient's medication record to verify dosing and check for drug-drug interactions. Nursing can provide patient counsel, monitor for interactions and adverse events, and report any issues to the prescriber. It is important to monitor renal function and levels of electrolytes regularly. Because there are many ACE inhibitors available today, it is important to keep up with the guidelines and recommendations, and the pharmacist can help the prescriber in this area.[25][6][26] An interprofessional team approach will optimize ACE inhibitor therapy resulting in improved patient outcomes. [Level V]


Watch the video: ACE Inhibitors and ARBs Anti-hypertensives in COVID-19. Coronavirus (January 2023).