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Review
. 2021 Aug 17;14(8):805.
doi: 10.3390/ph14080805.

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Enrique Ambrocio-Ortiz  1 , Gloria Pérez-Rubio  1 , Alma D Del Ángel-Pablo  1 , Ivette Buendía-Roldán  2 , Leslie Chávez-Galán  3 , Rafael de Jesús Hernández-Zenteno  4 , Alejandra Ramírez-Venegas  4 , Jorge Rojas-Serrano  5 , Mayra Mejía  5 , Rogelio Pérez-Padilla  4 , Cristóbal Guadarrama-Pérez  6 , Ramcés Falfán-Valencia  1
Affiliations
Review

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Enrique Ambrocio-Ortiz et al. Pharmaceuticals (Basel). .

Abstract

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1-7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1-7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.

Keywords: Angiotensin-Converting Enzyme 2 (ACE2); Coronavirus disease 2019 (COVID-19); angiotensin; renin-angiotensin system (RAS); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structure of ACE2. (A) Gene ACE2 conformed by 19 exons and 18 introns (3507 bp). (B) Alternative functional transcript without the last exon (3339). (C) Alternative transcript without the protein product (4 exons, 998 bp). (D) Alternative transcript without the protein product (3 exons, 786 bp). (E) Alternative transcript without the protein product (3 exons, 599 bp). Protein structure-based in PDB 1R42.
Figure 2
Figure 2
The organs and cells expressing ACE2.
Figure 3
Figure 3
Image of the possible substrates and products of Angiotensin-Converting Enzyme 2 (ACE2). ACE2 can affect Ang I and Ang II, producing Ang (1–9) and Ang (1–7), respectively. Ang (1–7) is a molecule with affinity for the Mas receptor (MasR), while Ang II is related to angiotensin II type 1 receptor (AT1R).
Figure 4
Figure 4
Regulated pathways of the nonclassical RAS axis. Angiotensin (1–7) (Ang (1–7)) can bind to Mas-related G-protein coupled receptor type D (MrgD) or Mas receptor (MasR). This interaction blocks the phosphorylation of the components of the two main pathways, Ras/Mitogen-activated protein kinase (MAPK) and Smad, resulting in the downregulation of apoptosis, cellular growth, tumor progression, inflammation, oxidative stress, reactive oxygen species, and mitochondrial stress. On the other hand, this interaction upregulates phosphatidylinositol-3-kinase (PI3K) to increase endothelial nitric oxide synthase (eNOS) phosphorylation, blocking the nicotinamide adenine dinucleotide phosphate reduced (NADPH) activity, decreasing the oxidative stress, and increasing the vasodilation. PLC: Phospholipase C; DAG: diacylglycerol; IP3: Inositol trisphosphate; IkB: inhibitor of nuclear factor kappa; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; IL-1β: interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; Bcl2: B-cell lymphoma 2; Ras: Rat sarcoma virus; AP-1: activator protein 1; AKT1: AKT serine/threonine kinase 1; ROS: reactive oxygen species.
Figure 5
Figure 5
Classical and nonclassical renin-angiotensin (RAS) axes. Biological effects of the classical (ACE/Ang II/AT1R) and nonclassical (ACE2/Ang (1–7)/MasR) axes. IL-1β: interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; Bcl2: B-cell lymphoma 2; IL-8: interleukin 8, TGF-β: Transforming growth factor beta; α-SMA: alpha smooth muscle actin; ROS: Reactive oxygen species; ERK1/2: extracellular signal-regulated protein kinase 1/2; NOS: Nitric oxide synthase.
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