ACE2: the molecular doorway to SARS-CoV-2

Abstract

The angiotensin-converting enzyme 2 (ACE2) is the host functional receptor for the new virus SARS-CoV-2 causing Coronavirus Disease 2019. ACE2 is expressed in 72 different cell types. Some factors that can affect the expression of the ACE2 are: sex, environment, comorbidities, medications (e.g. anti-hypertensives) and its interaction with other genes of the renin-angiotensin system and other pathways. Different factors can affect the risk of infection of SARS-CoV-2 and determine the severity of the symptoms. The ACE2 enzyme is a negative regulator of RAS expressed in various organ systems. It is with immunity, inflammation, increased coagulopathy, and cardiovascular disease. In this review, we describe the genetic and molecular functions of the ACE2 receptor and its relation with the physiological and pathological conditions to better understand how this receptor is involved in the pathogenesis of COVID-19. In addition, it reviews the different comorbidities that interact with SARS-CoV-2 in which also ACE2 plays an important role. It also describes the different factors that interact with the virus that have an influence in the expression and functional activities of the receptor. The goal is to provide the reader with an understanding of the complexity and importance of this receptor.

Keywords: ACE2; COVID-19; Coronavirus; SARS-CoV-2.

Fig. 1

ACE2 SNPs associated diseases reported in meta-analyses. 11 genetic variants are represented by different colors and have been associated with different diseases; rs2285666 and rs2106809 are the most frequent genetic variants, rs2285666 is correlated with essential hypertension, HDL-C, hsCRP, IMT and pulse pressure and rs2106809 is linked to diabetes mellitus (type 2), atrial fibrillation and hypertrophic cardiomyopathy. This figure was created using Server Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com

Fig. 2

Schematic overview of RAS and its biologic functions. Angiotensinogen is secreted by the liver and is converted to angiotensin I (AngI) via renin, a protease produced in the kidneys. AngI is subsequently converted to AngII by the catalytic action of angiotensin-converting enzyme (ACE), and binds to Angiotensin II Type 1 (AT1) and Type 2 (AT2) receptors. AngII binds to the angiotensin type 1 receptor (AT1R) to promote actions, such as vasoconstriction, cell hypertrophy, fibrosis, proliferation and inflammation. ACE2 converts Ang-I and Ang-II to angiotensin (1–7). Ang (1–7) binds to the MAS receptor (MASR) to promote actions of vasodilation, vascular protection, anti-fibrosis, anti-proliferation, anti-inflammation and anti-angiogenesis. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com

Fig. 3

A simplified scheme of the life cycle of SARS-CoV-2 inside the host cell (with organ injury in COVID-19). (1) SARS-CoV-2 requires activation by the serine protease TMPRSS2 for optimal cell entry and the viral Spike glycoprotein of the virion binds to the cellular receptor ACE2 and enters target cells through an endosomal pathway. (2) Following the entry of the virus into the host cell, the viral RNA is released into cytoplasm. (3) After release of the viral genome the viral polymerase protein is translated from the genomic RNA. (4) Replication occurs and new ssRNA(+) are synthesized. (5) In transcription, a nested set of sub-genomic RNAs (sgRNAs) is produced (6) Viral structural proteins (S, E, and M) are translated from the RNA inserted into the endoplasmic reticulum, N in citoplasm and move to the endoplasmic reticulum-Golgi intermediate compartment. (7) The viral proteins formed in ER migrate to the Golgi apparatus and are assembled with the nucleocapsid. (8) Formation of mature virion. Finally, (9) the virions are released via the constitutive exocytic pathway out of the cell. In the SARS-CoV-2 infection multi-organ are injured in COVID-19 patients. S, spike protein; E, envelope protein; M, membrane protein; N, nucleocapsid protein; ER, endoplasmic reticulum. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com

Fig. 4

ACE2 expression in different organs in healthy individuals and individuals with COVID-19. The figure represents ACE2 expression in normal organs and cells, such as cardiomyocytes, podocytes and hepatocytes, which are colored by its level of expression. The expression of ACE2 is gradually increased from healthy spleen to the highest expression in colon. The up-arrow indicates high expression in kidneys, lungs and heart of patients with COVID-19. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com

Fig. 5

Physiological and pathological of RAS axes and ACE2 in different organs. The figure summarizes the role of components of the RAS system axes in the control of the glycemia, insulin secretion, diabetic nephropathy and in cardiovascular disease in diabetes. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com