|Year : 2021 | Volume
| Issue : 3 | Page : 363-367
Angiotensin converting enzyme (ACE)-2: Beyond just the entry point for the SARS-CoV-2: A commentary
Viraj Suvarna1, Shashank Joshi2
1 Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India
2 Indian Academy of Physicians, Mumbai, Maharashtra, India
|Date of Submission||23-Jul-2020|
|Date of Acceptance||02-Dec-2020|
|Date of Web Publication||30-Sep-2021|
Dr. Viraj Suvarna
C-35, Rose Blossom, Sitladevi Temple Road, Mahim, Mumbai.
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Suvarna V, Joshi S. Angiotensin converting enzyme (ACE)-2: Beyond just the entry point for the SARS-CoV-2: A commentary. J Diabetol 2021;12:363-7
| Introduction and Objective|| |
Compared with angiotensin converting enzyme-1, or ACE as we know it, angiotensin converting enzyme-2 or ACE-2 was relatively unknown till SA
RS-CoV-2 brought it to the fore front. SARS (Severe Acute Coronary Syndrome)-CoV (Corona Virus)-1 virus used ACE-2 as its receptor for gaining entry into the respiratory tract epithelial cells. The virus for MERS or Middle East Respiratory Syndrome appeared in Saudi Arabia in 2012, and it is still smouldering, with 2494 cases and 858 deaths reported on the WHO website as of November 2019. MERS uses DPP-4 (Di-Peptidyl Peptidase) as its receptor, and now there are some reports linking the two receptors for SARS-CoV-2.
A one page correspondence, published in the Lancet Respiratory Medicine Journal, evoked a lot of controversy as it seemed to purport that patients on ACEi/ARB had upregulation of their ACE-2 which would mean more receptors for the SARS-CoV-2. The correspondence ended with a question mark, and in the correspondence the authors did use the word “hypothesis,” mentioned it needs to be confirmed and till then they only suggested monitoring the use of ACEi/ARB in COVID-19 hypertensive patients.
However, a closer look at what ACE-2 does in our body makes it clear that this enzyme converts angiotensin-2 to angiotensin 1–7, which has actions exactly opposite to that of angiotensin-2. Thus it balances the actions of angiotensin-2, namely, vasoconstriction, pro-proliferative, pro-inflammatory, pro-oxidative, and pro-fibrotic.This virus leads to down regulation of ACE-2 which leads to excess unopposed actions of angiotensin-2 which can contribute to the complications of COVID-19 such as acute respiratory distress syndrome (ARDS). Over expression or up regulation of ACE-2 can be protective as it generates angiotensin 1–7 (it also converts angiotensin-1 to angiotensin 1–9) and balances effects of angiotensin-2.
International and national hypertension, diabetes, endocrinology, and cardiology societies across the world have recommended that one should continue use of ACEi or ARBs in such patients because these drug classes have been shown to unequivocally have cardio-renal protective outcome benefits in patients with hypertension and/or diabetes. In April 2020, a study was published in Circulation Research which compared the outcomes in 1128 hypertensive COVID-19 patients across nine hospitals in China, and found that those who were on ACEi or ARBs had better survival (63–71% lesser mortality) when compared with those patients who were on other anti-hypertensive drug classes. Unadjusted mortality rate was lower in the ACEi/ARB group when compared with the non-ACEi/ARB group (3.7 vs. 9.8%; P = 0.01).
The objective of this narrative review article is to highlight implications of ACE-2 beyond it being a receptor for the binding of the Spike (S1) protein of the SARS-CoV-2.
| Diabetic Hypertensives|| |
Subsequently there was a publication which also purported that use of pioglitazone is beneficial in diabetic patients who get COVID-19 infection. The reasons cited were that up regulation of ACE-2 by the peroxisome proliferator activated receptor (PPAR)-gamma modulator is beneficial, as mentioned earlier. Plus pioglitazone has pleiotropic benefits such as anti-inflammatory, anti-oxidative, anti-atherosclerotic, anti-proliferative, and anti-fibrotic effects which can potentially modulate the cytokine storm and reduce cardiovascular complicationsof uncontrolled diabetes.
Vitamin D has also been recommended as a hormone to boost innate immunity (cathelicidins, defensins), correct vitamin D deficiency and insufficiency, and there have been some reports where serum vitamin D levels have been reciprocally correlated with severity of COVID-19 infections. Vitamin D is known to be a negative endocrine regulator of the renin–angiotensin–aldosterone system, and is associated with ACE-2 upregulation. In other words, patients with mild COVID-19 infections were found to have adequate serum 25(OH) vitamin D levels (212 patients—retrospective study) while patients with severe COVID-19 infections had lower serum 25(OH) vitamin D levels. The authors concluded that vitamin D status has been significantly associated with better clinical outcomes (P < 0.01).,
Hyperglycemia has been reported to be associated with worse prognosis in patients with COVID-19 mainly because of complications of uncontrolled diabetes, viz., inflammation (diab’it is’) and release of many mediators that contribute to the cytokine storm, oxidative stress, and immune system dysregulation. Also, it has been suggested that glycosylation of ACE-2 makes it easier for the virus to attach itself to this receptor. High and aberrantly glycosylated ACE-2 favors better intrusion of the virus and subsequently its fusion with the endosome, which means more viral replication, assembly, and release as well. Thus, one could expect higher chance of infection with this virus and greater severity of infection as well.
In the bi-directional syndemic alliance between diabetes and COVID-19, it can be hypothesized that SARS-CoV-2-mediated downregulation of ACE2 expression in the pancreas and peripheral tissues may decrease insulin secretion, increase insulin resistance, and induce hyperglycemia-induced RAS activation. On the other hand, ACE2 expression in the pancreas might facilitate SARS-CoV-2 invasion and direct β-cell damage.,
| Angiotensin Converting Enzyme-2|| |
Interestingly, recombinant human ACE-2 is being evaluated as a treatment for patients with COVID-19 infections, in animal studies and then in human beings, along with losartan. ACE-2 has also been detected in the lungs, heart, endothelium, liver, endocrine pancreas, testes, and the gastro-intestinal (GI) tract. This has been implicated in the inflammation of the endothelium (endothelialitis) which could lead to the microvascular thrombosis seen in severe COVID-19 patients. The virus has been detected in semen samples, and again ACE-2 expression in the Sertoli cells and interstitial cells of Leydig in the testes has been linked to this finding, which will be discussed further in the next paragraph.
| Gender Differences in Mortality and ACE-2 Expression|| |
Another aspect of ACE-2 that is being discussed is the gender differences in mortality due to COVID-19. Mortality among men with COVID-19 is higher than among women with COVID-19. ACE-2 is linked to TMPRSS-2 (Trans Membrane Protease Serine-2). TMPRSS2-ERG fusion gene is present in 40–80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. It is possible that this co-receptor, which primes ACE-2 for binding with the SARS-CoV-2, is expressed more in men, which could facilitate entry of the virus into the respiratory tract epithelial cells. A TMPRSS2 inhibitor (camostat mesylate) approved for clinical use blocked entry and might constitute a treatment option. Another reason could be that the gene which codes for ACE-2 is on the X sex chromosome and women have two X sex chromosomes.
A recently published article in the European Heart Journal reported on the circulating plasma concentrations of angiotensin converting enzyme-2 (ACE-2) in men and women with heart failure (BIOSTAT-CHF study), and found that plasma concentrations of ACE-2 were higher in men and lower in women. This had nothing to do with the fact that more men were on ACEi or ARB than women, but it could explain why men have a higher incidence and mortality than women if they get COVID-19 infections.
| Feco-oral Transmission and ACE-2 Expression in the GI Tract|| |
COVID-19 infection is typically characterized by respiratory symptoms, which indicates droplet transmission. However, several case studies have reported gastrointestinal symptoms and/or evidence that some patients with SARS-CoV-2 infection have viral RNA or live infectious virus present in faeces, which suggests that another possible route might be fecal–oral transmission. In a clinical characterization of 10 pediatric patients with SARS-CoV-2 infection in China, none of whom required respiratory support or intensive care and all of whom lacked signs of pneumonia, eight tested positive on rectal swabs, even after nasopharyngeal testing was negative. The details were published as a Brief Communication in Nature Medicine.
The patients, whose ages ranged from 2 months to 15 years, initially tested positive after being screened by nasopharyngeal swab real-time reverse transcriptase polymerase chain reaction PCR (RT–PCR). Next, the researchers conducted a series of nasopharyngeal and rectal swabs to investigate the pattern of viral excretion. Eight patients had real-time RT–PCR-positive rectal swabs. In addition, these eight patients had persistently positive rectal swabs even after their nasopharyngeal tests were negative. Four patients were discharged after two consecutive negative rectal swabs, but the rectal swabs of two of these patients later became positive again, despite nasopharyngeal tests remaining negative. Finally, the researchers used the viral RNA measurements to determine that viral shedding from the digestive system might be longer-lasting than that from the respiratory tract. The findings suggest that we may also need to use rectal swabs to confirm diagnosis of COVID-19.
There had been earlier reports, particularly in adults, of gastrointestinal symptoms and of the possibility of a fecal–oral route of transmission. In a cohort of 1099 patients with COVID-19 from 552 hospitals in China, published in the New England Journal of Medicine, 5.0% of patients presented with nausea or vomiting and 3.8% presented with diarrhea. Also, preliminary findings published in the American Journal of Gastroenterology found that of 204 patients with COVID-19 (mean age 54.9 years) who presented to three hospitals in China, 99 (48.5%) patients presented with digestive symptoms as their chief complaint. Sixty percent of patients without digestive symptoms were cured and discharged, compared with 34.3% of patients with digestive symptoms. In a short Research Letter published in the Journal of the American Medical Association, different tissues of patients with COVID-19 (n=1070 specimens from 205 patients of mean age 44 years) were tested by RT–PCR. Thirty-two percent of pharyngeal swabs (126 of 398) and 29% of fecal samples (44 of 153) tested positive. Electron microscopy of four SARS-CoV-2-positive fecal specimens detected live virus in stool samples from two patients who did not have diarrhea.
The precise mechanisms by which SARS-CoV-2 interacts with the gastrointestinal tract remain unknown. SARS-CoV-2 is thought to use ACE2 as a viral receptor, and ACE2 mRNA is highly expressed in the gastrointestinal system. In preliminary findings published in Gastroenterology, researchers examined clinical specimens from 73 hospitalized patients with SARS-CoV-2 infection. Thirty-nine patients tested positive for SARS-CoV-2 RNA in stool samples. In addition, 17 patients remained positive for SARS-CoV-2 in stool after becoming negative in respiratory samples. Viral host receptor ACE2 stained positive mostly in gastrointestinal epithelial cells.
Together, these findings have implications for our understanding of SARS-CoV-2 transmission. Asymptomatic children and adults may be shedding infectious virus and they could transmit it. Physicians and caretakers of potentially infected children need to be aware that stools might be infectious. The results are preliminary and further research is needed.
| ACE-2 and Symptoms of Anosmia, Ageusia|| |
Among the symptoms of COVID-19 (fever, cough, shortness of breath), six new symptoms have been added, two among which are sudden loss of the sense of smell (anosmia) or taste (ageusia).
There are a few hypothesized mechanisms of action on why COVID-19 patients may develop anosmia and ageusia despite their association with SARS-CoV-2 not having been yet established. It could be due to direct damage of the virus on olfactory and gustatory receptors. The nasal epithelium contains olfactory epithelium (OE) and olfactory sensory neurons (OSNs). OE contains basal stem cells that are responsible for renewing sustentacular cells and OSNs. It also contains microvillar cells and mucus-secreting Bowman’s gland cells. Sustentacular cells structurally support sensory neurons, detoxify, and maintain the salt and water balance. It is thought that SARS-CoV-2 infects cells through interaction between its spike (S) protein and the angiotensin-converting enzyme 2 (ACE2) protein on target cells. This interaction requires cleavage of the S protein by the cell surface protease TMPRSS2. Therefore, ACE2 and TMPRSS2 are required for SARS-CoV-2 to infect cells. The study of mouse and human RNA sequencing datasets by Brann et al. showed that OE expresses two key genes required for SARS-CoV-2 entry: ACE2 and TMPRSS2. OSNs, on the contrary, did not show any gene expression.
Sustentacular cells in OE express these genes at levels comparable to those found in lung cells. Thus, it suggests that SARS-CoV-2 may infect OE that contains sustentacular cells, leading to damage of OE and disturbing the function of OSN. Loss of sustentacular cells and the inability to regenerate OE over time can result in long-lasting anosmia. In addition, damage to microvillar cells in OE might alter iron gradients and thus affect the function of sensory neurons. Damage to the Bowman’s gland cells could cause disruption of the olfactory neuroepithelium. However, due to the relatively new identification of SARS-CoV-2-associated anosmia, no formal experiments have been performed to explore SARS-CoV-2’s influence on OE. Moreover, it is unclear whether the olfactory abnormality is due to dysfunction in the higher-order olfactory structures. It has shown previously that viruses including coronavirus can propagate to olfactory bulb or piriform complex even though the exact mechanisms of action are unknown. It is also unclear whether the impact of SARS-CoV-2 on smell is responsible for the alteration in taste perception.
| ACE-2 and Influenza|| |
A new study, published as a letter to the New England Journal of Medicine, further focused attention on how the renin–angiotensin system—and specifically the ACE2 receptor—may be involved in COVID-19 infection. The authors studied the relationship between ACE-inhibitor and ARB use and influenza A infection in a large United Kingdom patient database, and noted that influenza A has been shown to use the ACE2 receptor to mediate lung damage, similar to that seen in severe acute respiratory syndrome (SARS) with COVID-19. Understanding the shared mechanism between SARS and influenza may help to address the question as to how ACE inhibitors and ARBs may modulate the manifestations of certain viral respiratory infections.
Results showed that during a median 8.7 years of follow-up, individuals who had received a prescription for an ACE inhibitor had a lower risk of influenza than those who had not (adjusted hazard ratio, 0.66). A second analysis found that the longer the duration of ACE-inhibitor use, the lower the risk of influenza infection. Similar results were found for ARBs.
These associations regarding observed susceptibility to influenza may reflect mechanisms that are shared with coronaviruses, including SARS-CoV-2.
| Tissue Versus Plasma ACE-2|| |
In an editorial accompanying the European Heart Journal publication, Gavin Oudit, MD, University of Alberta, Edmonton, Canada, and Mark Pfeffer, MD, Brigham and Women’s Hospital, Boston, Massachusetts, suggested that further work should measure plasma angiotensin peptides and plasma ACE2 levels and activity in COVID-19 patients to provide a direct evaluation of the state of the renin–angiotensin system, which could guide therapeutic interventions. Oudit, who has researched extensively on ACE2, put forward a hypothesis that the COVID-19 virus could be bringing about its harmful effects by causing an over-activation of the renin–angiotensin system. He explained that higher plasma levels of ACE2 may actually reflect lower tissue levels. Tissue ACE2 is beneficial. It is nature’s own inhibitor of the renin–angiotensin system, breaking down harmful angiotensin II to the protective angiotensin 1–7. The enzyme A Disintegrin and Metalloprotease (ADAM)-17 is the key to regulating tissue and plasma ACE2 levels. This enzyme, which is thought to be more active in men than women, cleaves tissue ACE2 to form plasma ACE2, and it is believed that the virus responsible for COVID-19 activates ADAM-17. Activation of ADAM-17 is detrimental on two levels. It directly causes a super inflammatory response, and it also reduces cardioprotective ACE2 in tissue.
Oudit believes the role of ACE2 in COVID-19 infection has been misunderstood. The virus does bind to ACE2 to enter cells, but only a small amount of ACE2 is needed for this. Higher levels are needed to protect from cardiovascular disease. By activating ADAM-17 the virus causes shedding of ACE2 from tissue into plasma, and the reduction of ACE2 in tissue leads to over-activation of the renin–angiotensin system in tissues, which causes cardiovascular disease to get worse. He believes there has been a lot of misinformation surrounding COVID-19, which has included speculation about ACE inhibitors and ARBs. The science suggests that these drugs are more likely to be beneficial than harmful. Observational clinical studies reported so far support this view. The renin–angiotensin system is being over-activated by the virus, and this could also explain why patients with underlying cardiovascular diseases are having worse outcomes and would suggest that taking an ACE inhibitor or ARB would actually be protective. The influenza virus may also activate the renin–angiotensin system. That study suggests that ACE inhibitors and ARBs may be protective here as well.
ADAM17 activation by SARS‐CoV‐2 might also increase the risk of hyperglycemia. ADAM17 plays a potential role in inflammation, as it can cleave and thereby activate a variety of cytokines and cytokine receptors including tumor necrosis factor α (TNFα) and the interleukin-6 receptor (IL-6R). Increased inflammation might also contribute to the development of islet β-cell failure. Accumulating evidence suggests that patients with severe COVID-19 and ARDS might have a cytokine storm syndrome, including high levels of IL-6 and TNFα. Meanwhile, RAS activation can propagate acute lung injury.
ADAM17 is involved in the shedding of transmembrane ACE2 to release the catalytically active ectodomain into the circulation. ADAM17-mediated ectodomain shedding might compromise the RAS compensatory axis by impairing ACE2 enzymatic activity or its ability to process angiotensin II on the cell surface. In humans, urinary ACE2 levels are significantly higher in insulin-resistant subjects and type 2 diabetes mellitus than in controls with normal glucose tolerance. In addition, urinary ACE2 appears to be positively associated with inflammatory cytokines, resembling increased ACE2 shedding.
| Conclusion|| |
To summarize, ACE-2 is a receptor for this novel Corona virus 2019, SARS-CoV-2 but at the same time, it is also present all over the body in various tissues/organs. So it is not just an entry point for this virus. This paper has presented evidence that ACE-2 could be linked to the protean manifestations of this ever evolving disease. Use of drugs such as RAAS blockers or thiazolidinediones or vitamin D that can lead to upregulation of ACE-2 were initially thought to be unsafe, but subsequently have been shown to be beneficial in COVID-19 patients with hypertension and diabetes. We need to continue treatment with drugs that have shown, unequivocally, that their proven benefits far outweigh any possible risk based on hypotheses that has at best minimal in vitro evidence. Nevertheless, these are dynamic times, medicine is an ever evolving science and we need to sift the wheat from the chaff and distinguish between evidence-based and evidence-biased medicine, where the trained eye (i) can make all the difference, along with clinical acumen and patient values.
Financial support and sponsorship
Conflict of interest
There are no conflicts of interest.
| References|| |
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020. https://doi.org/10.1016/PII
Cheng VC, Lau SK, Woo PC, Yuen KY. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 2007;20:660-94.
MERS Situation Update. November 2019. Available at: http://www.who.int (last accessed on Aug 06, 2021).
Drucker DJ. Coronavirus infections and type 2 diabetes—shared pathways with therapeutic implications. Endocrine Rev 2020;41. doi: 10.1210/endrev/bnaa011. https://academic.oup.com/edrv
Hasenfuss G, Mann DL, editors. Chapter 23. Pathophysiology of heart failure. In: Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli G, Braunwald E, editors. Braunwald’s Heart Disease a Textbook of Cardiovascular Medicine. 11th ed. Amsterdam: Elsevier Inc; 2019. p. 445.
Hughes S. New angiotensin studies in COVID-19 give more reassurance. Medscape. https://www.medscape.com/viewarticle/929992 (last accessed on May 10, 2020).
Fosbel EL, Butt JH, Ostergaard L, Andersson C, Selmer C, Kragholm K, et al
. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA doi:10.1001/jama.2020.11301. Published online on June 19, 2020.
Zhang P, Zhu L, Cai J, Lei F, Qin J-J, Xie J, et al
. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. doi:10.1161/circresaha.120.317134.
Carboni E, Carta AR, Carboni E. Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19? Med Hypotheses 2020;140:109776.
Alipio M. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019(COVID-19) (April 9, 2020). Available at SSRN: https://ssrn.com/abstract=3571484 or http://dx.doi.org/10.2139/ssrn.3571484 (last accessed on Aug 06, 2021).
Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus 2019 infection and mortality. April 15, 2020. Aging Clinical and Experimental Research https://doi.org/10.1007s40520-020-01570-8. Springer Nature, Switzerland.
Ceriello A. Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory. Diabetes Res Clin Pract 2020;163:108186.
Pal R, Bhadada SK. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diab Metab Syndrome 2020. doi: 10.1016/j.dsx.2020.04.049.
Nakhleh A, Shehadeh N. Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review. Diabetes Metab Syndr 2020;14:509-12.
https://clinicaltrials.gov/ct2/show/NCT04287686 (last accessed on May 10, 2020).
Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with Coronavirus Disease 2019. JAMA Network Open 2020;3:e208292. doi: 10.1001/jamanetworkopen.2020.8292.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al
. SARS-cov-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.
Sama IE, Ravera A, Santema BT, Goor HV, Maaten JM, Cleland JGF, et al
. Circulating plasma concentrations of angiotensin converting enzyme-2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J 2020;0:1-8. doi: 10.1093/eurheartj/ehaa373
Hindson J. COVID-19: Feco-oral transmission? Nat Rev Gastroenterol Hepatol 2020. https://doi.org/10.1038/s41575-020-0295-7.
Zhang Q, Shan KS, Abdollahi S, Nace T. Anosmia and ageusia as the only indicators of Coronavirus Disease 2019 (COVID-19). Cureus 12:e7918. doi: 10.7759/cureus.7918.
Chung SC, Providencia R, Sofat R. Association between angiotensin blockade and incidence of influenza in the United Kingdom. N Engl J Med 2020;383:397-400.
Oudit GY, Pfeffer MA. Plasma angiotensin-converting enzyme 2: Novel biomarker in heart failure with implications for COVID-19. Eur Heart J 2020;41:1818-20.