Last update and review: August 10, 2020.
A short summary.
SARS-CoV-2 can infect cells that prominently express angiotensin-converting enzyme 2 (ACE2), a plasma membrane-bound ectoenzyme. Below, we share our notes on what angiotensin-converting enzyme 2 is and on its role in human physiology.
ACE2 is a plasma membrane-bound ectoenzyme.
Brigitte A Wevers & Lia van der Hoek, 2010 (1):
To infect its target host cells, SARS-CoV utilizes ACE2, the RAS component now known to orchestrate protection from acute lung failure/ARDS.
The functions of ACE2 in human physiology.
Varagic et al., 2014 (2):
Angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1–7).
Similar to ACE, ACE2 is a plasma membrane-bound ectoenzyme, although soluble forms in plasma and urine are also found. ACE2 metabolizes Ang I and Ang II into Ang-(1–9) and Ang-(1–7) respectively with higher preference for Ang II degradation.
An extended citation from Varagic et al., 2014 (2) on ACE2 role in angiotensin II/Angiotensin-(1-7) balance of the RAS.
The conventional vs. alternate RAS.
The conventional RAS has been viewed as a classical hormonal system comprising the enzymatic cleavage of the decapeptide angiotensin I (Ang I) in the circulation by renal renin from liver-derived angiotensinogen. Further cleavage of two amino acids from the Cterminal part of Ang I by angiotensin converting enzyme (ACE) primarily in the pulmonary circulation leads to formation of Ang II, which contributes to the regulation of blood pressure by influencing vascular smooth muscle cells and sodium and volume homeostasis as well as aldosterone secretion. The Ang II effects are mediated through its two known plasma membrane receptors, angiotensin type 1 (AT1) and AT2 receptors. There is some controversy about the outcome of AT2 activation but a majority of reports point toward opposing actions of AT1 and AT2 on vascular tone and sodium homeostasis. As opposed to this classical endocrine system, where the action of the hormone takes place quite remotely from its origin, the concept of the local tissue RAS with paracrine, autocrine, and intracrine actions has become increasingly appreciated in the last two decades, underlining more the role of RAS in regulating cell growth and proliferation, inflammation, and cytokine production. Indeed, a growing body of evidence testifies that each and every component of the RAS is found throughout diverse tissues and organs including the heart, vasculature, kidneys, brain, lung, and reproductive tissues. Importantly, recent studies identifying new enzymes (ACE2) or new substrates for known enzymes (chymase, ACE), peptides [Ang-(1-12), Ang-(1-9), Ang-(1-7)], and receptors (renin/prorenin receptor, mas receptor) have added a novel insight into the role of RAS in pathophysiology of hypertension and related cardiovascular and renal disease.
ACE2/Ang-(1-7)/mas axis.
The heptapeptide Ang-(1-7) [Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -] is a truncated form of Ang II lacking phenylalanine in the eighth position. Its functional role in counterbalancing Ang II actions has been recognized far before the discovery of its forming enzyme ACE2 and related receptor mas. As reviewed before (4;5), Ang-(1-7) induces systemic and regional vasodilation, diuresis and natriuresis, and exerts antiproliferative and antigrowth effects in vascular smooth muscle cells, cardiac myocytes and fibroblasts as well as glomerular and proximal tubular cells. Cardiorenal protective effects of Ang-(1-7) are mediated by the mas receptor through different signaling pathways including several autocoids, MAPK, AKT, NADPH oxidase, TGF-β1, EGF receptor, and NF-kapaB activity. ACE2 was discovered in 2000 as a homologue enzyme to the better-known ACE sharing many features of the enzymes belonging to a family of zinc metalloproteinases.
ACE2 was discovered in 2000 as a homologue enzyme to the better-known ACE sharing many features of the enzymes belonging to a family of zinc metalloproteinases. Similar to ACE, ACE2 is a plasma membrane-bound ectoenzyme, although soluble forms in plasma and urine are also found (6;7). Shedding of ACE2 has been frequently associated with the activity of tumor necrosis factor alpha converting enzyme (TACE) (8). In contrast to ACE, which has two active-site domains and acts as dicarboxipeptidase, ACE2 expresses only one catalytic site and acts as a monocarboxypeptidase, removing one amino acid from the Cterminus of its substrates. ACE2 metabolizes Ang I and Ang II into Ang-(1-9) and Ang-(1-7) respectively with higher preference for Ang II degradation (9). Other known ACE2 substrates belong to the apelin family (apelin 13, apelin 17, apelin 36) which, in addition to Ang-(1-7), exert important protective cardiovascular actions (10). ACE2 is also insensitive to known ACE inhibitors (11;12).
Conclusions of Varagic et al., 2014 (2) on ACE2.
Experimental and clinical studies continue to provide novel evidence on the crucial role of ACE2/Ang-(1-7) in counterbalancing vasoconstrictor/hypertophic/proliferative effects of Ang II determining the onset and progression of hypertension and cardiorenal damage. Additional studies are needed to advance initial progress on the pharmacological and genetic therapeutic approaches to enhance ACE2 activity aiming to decrease Ang II while increasing Ang-(1-7) actions. This may be of particular interest when complete suppression of Ang II in response to the therapy with ACEI or AT1 receptor antagonist is not achieved or when alternative Ang II synthetic pathways are overactive. Further research is needed to confirm whether serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease.
Related:
Selected references:
1. Brigitte A Wevers & Lia van der Hoek. Renin–angiotensin system in
human coronavirus pathogenesis. Future Virol. (2010) 5 (2), 145–161
2. Varagic J, Ahmad S, Nagata S, Ferrario CM. ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury. Curr Hypertens Rep. 2014;16(3):420. doi:10.1007/s11906-014-0420-5
3. Santos et al., Journal of Endocrinology (2013)216, R1–R17.
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