Twenty years of progress in angiotensin converting enzyme 2 and its link to SARS-CoV-2 disease

Abstract

The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.

Keywords: angiotensin II; angiotensin-(1-7); cardiovascular disease; chymase; coronavirus; innate immunity.

Figure 1

Biochemical pathways accounting for the generation of the main biologically active angiotensin peptides Black lettering denotes primary enzymatic pathways; blue text denotes alternate enzymatic pathways. Brown lines represent the pressor, proliferative, prothrombotic, and angiogenic pathways leading to generation of Ang II and Angiotensin A. Blue lines denote the biochemical pathways for the opposing arm of the RAS for which Ang-(1–9), Ang-(1–7), and alamandine [Ala-Ang-(1–7)] are the active peptides. K_cat/K_m is the rate constant for conversion of free substrate into product (unit’s values are M⁻¹ × s⁻¹). Data on pathways derived from authors’ research [,–178], and studies reported by others [10,49,179]. Abbreviations as denoted in text. ¹Kallikrein or a kallikrein-like enzyme [180,181].

Figure 2

Schematic overview of the intracellular signaling molecules mediating Ang II actions on vascular smooth muscle constriction (brown arrows), transcription, growth and protein synthesis (blue arrows) vs. the signaling pathways (green arrows) activated by Ang-(1–7) which limits AT₁-R pathway activation through stimulation of antioxidant responses mediated by NO production, prostaglandin synthesis, and reduction in the rate of Ang II metabolism by membrane anchored ACE2Activation of MAP kinases ERK1/2 via the G-coupled AT₁-R promotes transactivation of the EGF receptor and stimulation of Ras-dependent and Ras-independent pathways [182]. Ang-(1–7) binding to the Mas receptor activates endothelial NO synthase (eNOS) mediated stimulation of NO via a protein kinase B (Akt)-dependent pathway. Ang-(1–7) stimulates dose-dependent release of cAMP by prostacyclin-mediated activation of adenylate cyclase. This signaling pathway causes suppression of Ang II stimulation of MAP kinase activities (ERK1/2). Dephosphorylation of MAP kinases by Ang-(1–7)- stimulation of DUSP-1 counteracts Ang II-mediated agonist actions. Pathways represented in the diagram summarized from studies reported in references [,,,–187,39,183,188]. Abbreviations: cAMP, cyclic adenosine monophosphate; EGF, epidermal growth factor.

Figure 3

A systemic chronic inflammatory response emerges as a major factor in the etiology of diseases including those affecting the cardiovascular system. The RAS through the signaling mechanisms conveyed by opposing functions of Ang II and Ang-(1–7) emerge as a critical element in modulating the expression of inflammatory cytokines and chemokines [,,,,–193]. Activation of immune mechanisms in response to viruses, bacteria, toxins, and neuroendocrine factors (hormones) activate specific responses which augment the transcription of proinflammatory factors such as the nuclear factor NF-κB and consequent production and release of cytokines and chemokines. Ang II production in response to heightened level of oxidative stress shifts the balance between the ACE/Ang II/AT₁-R and ACE2/Ang-(1–7)/Mas-R axis in favor of augmented transcription of NF-κB and release of various cytokines from the interleukin (IL)-1 (IL-1) family (IL-6, IL-18, IL-36, IL-1β) and chemokines (MCP-1, VCAM-1, VGEF). The positive feedback between oxidative stress-mediated Ang II actions and IL-6 facilitates increase angiotensinogen (AGT) synthesis in peripheral organs [194,195]. The surge in Ang II activity down-regulates ACE2 activity 2 with a consequent decrease in the antihypertensive, antiproliferative, anti-inflammatory Ang-(1–7) mechanisms mediated by the Mas receptor [37,38]. Ang II cellular production in monocytes and bone-marrow derived macrophages and lymphocytes [,–198] contribute to the liberation of chemokines with consequent occurrence of vascular endothelial dysfunction, increased radical oxygen species metabolism of nitric oxide synthesis, and cellular senescence with accompanying collagen production and fibrosis [34]. The picturesque outline of mechanisms associated with activation of innate immunity includes a relatively unrecognized existence of alternate biochemical mechanisms for intracellular Ang II production independent of ACE and mediated by the metabolism of angiotensin-(1–12) [Ang-(1–12)] into Ang II either directly or through the intermediate step of the cleavage of Ang I by mast-cell generated chymase [169,199,200]. Other abbreviations: DC, dendritic cell; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cell; PBMC, peripheral blood mononuclear cell; VCAM-1, vascular cell adhesion molecule 1; VGEF, vascular endothelial growth factor.