Editor’s note: We hope our medical student readers will find this review helpful, informative and concise. Please see the list of references for further reading.
Introduction
SARS-CoV-2, the virus that causes COVID-19, shares a high degree of homology with SARS-CoV, including sharing the receptor protein ACE2.
Review of selected pathways of RAS: ACE2 plays a counter regulatory role to ACE
Angiotensin converting enzyme 2 (ACE2) was first reported in 2000 and is related to its better-known cousin, angiotensin converting enzyme (ACE). ACE2 is a transmembrane metalloproteinase that is highly expressed in lung alveolar epithelial cells and enterocytes of the small intestines [1,2].
The function of ACE2 is to counter-regulate the renin-angiotensin-system (RAS) in a pathway termed the alternative RAS or non-classical system [3,4]. RAS is an important hormonal axis for the regulation of blood pressure and volume. ACE catalyzes the conversion of angiotensin I to angiotensin II, primarily in the lungs. Angiotensin II is a potent vasoconstrictor that acts on the angiotensin II receptor type 1 or type 2 (AT1 and AT2). Angiotensin II also increases vascular permeability [5].
The non-classical RAS pathway functions by opposing RAS activity. One of the ways ACE2 accomplishes this is by converting angiotensin II to angiotensin 1-7, a vasodilator that acts via the Mas receptor. Clinically, ACE2 has emerged as a potential therapeutic agent for the treatment of hypertension and cardiovascular disease [6].
Relationship of common antihypertensives on ACE2 levels: ACE inhibitors and ARBs
ACE inhibitors and angiotensin receptor blockers (ARBs) are commonly used classes of antihypertensives that interfere with the RAS pathway at various points. ACE inhibitors such as lisinopril directly inhibit the conversion of angiotensin I to angiotensin II by ACE. Despite a high degree of homology between ACE and ACE2, it has been demonstrated that ACE inhibitors have no effect on the function of ACE2 [9]. ARBs such as losartan, on the other hand, function downstream in this pathway by antagonizing the angiotensin II type 1 receptor. It is unlikely that ARBs have any direct impact on ACE2.
Despite the lack of direct effects of ACE inhibitors/ARBs on ACE2 levels, an important indirect effect is the possible upregulation of ACE2. Studies in rats demonstrated increased cardiac ACE2 activity in response to treatment with lisinopril or losartan [10,11]. Limited evidence in humans suggest that olmesartan may be uniquely responsible for this effect [12].
Rationale for the inhibition of viral entry
Coronaviruses are so named for the “crown-like” spike (S) proteins that line their surface and are responsible for interacting with receptor proteins on host cells. Based on its similarities to SARS-CoV, it was suggested early on that the SARS-CoV-2 S protein interacts with ACE2 to mediate entry into cells [7]. There is now clear evidence, including structural modeling of the S protein:ACE2 interface, that suggests ACE2 is the main point of viral entry [8].
Several proposed and seemingly contradictory theories exist regarding inhibition of viral entry into cells based on the ACE2 receptor. The rationale behind the two general approaches will be discussed. It is important to stress that the following discussion is theoretical and based only on what is known about the pathophysiology of the disease process.
1. Decreased ACE2 may be protective against SARS-CoV-2
As the viral receptor mediating cell entry, it is rational to suggest that a blockade of ACE2 may interfere with viral pathogenesis. It has recently been suggested that many important comorbidities that are associated with increased case fatality or severe disease rate have indications for ACE inhibitor/ARB use [13,14]. These comorbidities include hypertension, diabetes and cardiovascular disease. Under this line of reasoning, ACE inhibitor/ARB use may be considered a risk factor for the virus due to potentially increased levels of ACE2, which may facilitate viral entry which may contribute to the observed increased mortality.
From a pathophysiological standpoint it is therefore important to consider the consequences of a therapeutic ACE2 blockade, which include uncontrolled RAS activation. This point will be explored further in the next section.
2. Increased ACE2 may be protective against severe infections
The seemingly paradoxical suggestion that increased levels of ACE2 may be protective comes from a consideration of downstream pathophysiology. As explained by Gurwitz [15], binding of SARS-CoV-2 to ACE2 leads to ACE2 downregulation and increased RAS activity [16]. Increased levels of angiotensin II lead to increased vascular permeability, which has been shown to contribute to acute respiratory distress and may result in poorer outcomes [17]. This line of reasoning would suggest that ACE inhibitors/ARBs actually have a protective effect against severe SARS-CoV-2 infections due to the upregulation of ACE2 and the subsequent inhibition of angiotensin II mediated pulmonary injury.
A related intervention using the same line of reasoning is the use of soluble ACE2. Soluble ACE2 would theoretically have a neutralizing effect on SARS-CoV-2 by occupying the S protein binding site on the virus while also offering protective effects against angiotensin II.
A consideration for the use of soluble ACE2 is whether infected patients are hemodynamically stable enough to tolerate the hypotensive effects that may result from increased ACE2.
Conclusion
The pathophysiology of SARS-CoV-2 is similar to that of SARS-CoV. Current attempts to understand the novel virus and identify potential therapeutic options benefit tremendously from the existing research available on SARS-CoV. Based on the known pathophysiology of SARS-CoV-2 viral entry it appears likely that ACE2 levels have a variable affect at different times in the disease course. Decreased ACE2 levels may inhibit initial viral entry while increased levels may reduce severe complications in those already infected. These conclusions are based entirely on a theoretical examination of viral pathophysiology. At this time, in the absence of direct evidence, it is unwise to suggest modification of hypertensive medication. This recommendation is endorsed by cardiovascular societies in Canada (CCS), the United States (AHA, ACC, HFSA), and Europe (ESC). The role of RAS regulation is ultimately unclear and further research will be needed to elucidate clinically effective targets for preventing drug entry.
Author’s comment: This commentary was meant to provide a basic review and summary of the viral entry mechanisms of the SARS-CoV-2 virus and theoretical targets for intervention. It is meant to serve as a primer for readers to better understand the basics of the viral pathophysiology and to be able to better engage with new research as it emerges. This article was motivated by a series of Rapid Responses in the British Medical Journal [18–20] that collectively demonstrated incomplete information and confusion on this topic. The extraordinary volume of knowledge being generated and the ease of communication in the modern era represent both a great strength, but also potential weakness of the biomedical community at this time. Whether you are looking at scientific literature or popular media, please read critically and carefully to help limit the spread of misinformation.
References
1. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. doi:10.1002/path.1570
2. Donoghue M, Hsieh F, Baronas E, et al. UltraRapid Communication A Novel Angiotensin-Converting Enzyme – Related to Angiotensin 1-9. Circ Res. 2000;87:e1-e9.
3. Yim HE, Yoo KH. Renin-angiotensin system – Considerations for hypertension and kidney. Electrolyte Blood Press. 2008;6(1):42-50. doi:10.5049/EBP.2008.6.1.42
4. Chappell MC. The Non-Classical Renin-Angiotensin System and Renal Function. Compr Pyhsiol. 2012;2(4):2733-2752. doi:10.1038/jid.2014.371
5. Williams B, Baker AQ, Gallacher B, Lodwick D. Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension. 1995;25(5):913-917.
6. Chamsi-Pasha MAR, Shao Z, Tang WHW. Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep. 2014;11(1):58-63. doi:10.1007/s11897-013-0178-0
7. Gralinski LE, Menachery VD. Return of the coronavirus: 2019-nCoV. Viruses. 2020;12(135):1-8. doi:10.3390/v12020135
8. Yan R, Zhang Y, Guo Y, Xia L, Zhou Q. Structural basis for the recognition of the 2019-nCoV by human ACE2. Science (80- ). 2020;(March). doi:10.1101/2020.02.19.956946
9. Turner AJ, Tipnis SR, Guy JL, Rice GI, Hooper NM. ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors. Can J Physiol Pharmacol. 2002;80(4):346-353. doi:10.1139/y02-021
10. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605-2610. doi:10.1161/CIRCULATIONAHA.104.510461
11. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of Angiotensin-Converting Enzyme 2 after Myocardial Infarction by Blockade of Angiotensin II Receptors. Hypertension. 2004;43(5):970-976. doi:10.1161/01.HYP.0000124667.34652.1a
12. Furuhashi M, Moniwa N, Mita T, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015;28(1):15-21. doi:10.1093/ajh/hpu086
13. Sommerstein R. Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. The British Medical Journal. https://www.bmj.com/content/368/bmj.m810/rr-2.
14. Fang L, Karakiulakis G, Roth M. Correspondence hypertension and increased risk for. Lancet Respir. 2020;2600(20):30116. doi:10.1016/S2213-2600(20)30116-8
15. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020;(February):2-5. doi:10.1002/ddr.21656
16. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. doi:10.1038/nm1267
17. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112-116. doi:10.1038/nature03712
18. M. A. P, S. S. Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections – Novel mode of treatment. The British Medical Journal. https://www.bmj.com/content/368/bmj.m406/rr-2.
19. Akamatsu A. Re: Response to the emerging novel coronavirus outbreak. Br Med J. https://www.bmj.com/content/368/bmj.m406/rr-7.
20. Donelli D. Inappropriate ARBs and ACE inhibitors prescription for COVID-2019 infection prevention. Br Med J. https://www.bmj.com/content/368/bmj.m406/rr-11.
Image credit: Medical Research Scholars Working in Lab (CC BY-NC 2.0) by National Institutes of Health (NIH)
Contributing Writer
Schulich School of Medicine & Dentistry
Chris Zhang is a second year medical student at the Schulich School of Medicine & Dentistry in London, Ontario class of 2022. In 2018, he graduated from McMaster University with a Bachelor of Science in biochemistry. Within medicine he enjoys learning new things and doing his best to make a difference. Outside of medicine, he enjoys basketball, crochet, and stories. In the future Chris would like to pursue a career in surgery.