The Impact of Angiotensin-Converting Enzyme-2/Angiotensin 1-7 Axis in Establishing Severe COVID-19 Consequences

Abstract

The COVID-19 pandemic has put a tremendous stress on the medical community over the last two years. Managing the infection proved a lot more difficult after several research communities started to recognize the long-term effects of this disease. The cellular receptor for the virus was identified as angiotensin-converting enzyme-2 (ACE2), a molecule responsible for a wide array of processes, broadly variable amongst different organs. Angiotensin (Ang) 1-7 is the product of Ang II, a decaying reaction catalysed by ACE2. The effects observed after altering the level of ACE2 are essentially related to the variation of Ang 1-7. The renin-angiotensin-aldosterone system (RAAS) is comprised of two main branches, with ACE2 representing a crucial component of the protective part of the complex. The ACE2/Ang (1-7) axis is well represented in the testis, heart, brain, kidney, and intestine. Infection with the novel SARS-CoV-2 virus determines downregulation of ACE2 and interrupts the equilibrium between ACE and ACE2 in these organs. In this review, we highlight the link between the local effects of RAAS and the consequences of COVID-19 infection as they arise from observational studies.

Keywords: ACE2; Ang (1-7); COVID-19; RAAS; angiotensin 1-7; angiotensin-converting enzyme-2; long-term effects; renin-angiotensin-aldosterone system.

Figure 1

Schematic representation of RAAS components, their main receptors, and main actions. Deleterious side is shown in red-rimmed boxes; protective side is shown in green-rimmed boxes. Abbreviations: Agen, angiotensinogen; Ang, angiotensin; ACE, angiotensin-converting enzyme; Decarb, unspecified decarboxylases; MasR, Mas receptor pathway; MrgD, Mas-related G protein coupled receptor; AT, angiotensin receptor.

Figure 2

Schematic depiction of the modern view ACE2 axis and its products. AGen, angiotensinogen; Ang, angiotensin; ACE, angiotensin-converting enzyme; Decarb, unspecified aspartate decarboxylases; THOT, thimet oligopeptidase; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; MasR, Mas axis; MrgD, Mas-related G protein receptor; AT–R, angiotensin receptor subtype.

Figure 3

Comparative mechanisms of Ang II and Ang (1-7). Ang, angiotensin; MrgD, Mas-related G protein receptor D; AT1-R, angiotensin receptor type I; GTP, guanosine triphosphate; GDP, guanosine diphosphate; PLC, phospholipase C; PKC, protein kinase C; DAG, diacylglycerol; IP3, triphosphate inositol; Ca Ch, Calcium channel of smooth endoplasmic reticulum; eNOS, endothelial nitric oxide synthase; nNOS, neuronal; PI3K/Akt pathway; PDK1, phosphoinositide-dependent protein kinase 1.

Figure 4

An extensive scheme displaying the mechanisms Ang (1-7) influences on an intracellular level. β-arr1/2, β-arrestins; GSK3β, glycogen synthase kinase 3β; AS160, Akt substrate 160; IRS-1, insulin receptor substrate 1; PGI, PGE, prostaglandins; NHE3, sodium hydrogen exchanger 3; NF-KB, nuclear transcription factor; iNOS, inducible nitrous oxide synthase; MAPK, mithogen-activated protein kinase; NADPH, nicotin-amide-diphospho-hydrogenase.

Figure 5

A summary of the previously described consequences of COVID-19 infection.