Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic

Abstract

Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7), angiotensin (1-9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.

Keywords: ACE2; COVID-19; Counter-regulatory renin-angiotensin system; Hypertension.

Graphical abstract

Fig. 1

Classical and counter-regulatory renin-angiotensin system (RAS). Left: The classical RAS pathway. Angiotensinogen (AGT) can be cleaved by renin to form angiotensin I (Ang I). Ang I is converted by angiotensin-converting enzyme (ACE) to generate angiotensin II (Ang II). Ang II activates the Ang II type-1 receptor (AT1R) and the Ang II type-2 receptor (AT2R). The activation of AT1R leads to increased blood pressure, cardiac hypertrophy and fibrosis, vascular inflammation and remodeling, end-stage organ failure, decreased nitric oxide (NO) bioavailability and interrupted renal water-sodium balance. Moreover, Ang II can also produce angiotensin A (Ang A) with the action of aspartate decarboxylase (AD). Right: The counter-regulatory RAS pathway. Angiotensin-converting enzyme 2 (ACE2) is considered as the core component of the counter-regulatory arm of the RAS, catalyzing the following three reactions: a) cleavage of Ang II to Ang (1–7); b) breakdown of Ang I to Ang (1–9); and c) cleavage of Ang A to alamandine. Alternatively, Ang(1–7) can be formed from Ang (1–9) cleavage by ACE, neutral endopeptidase (NEP), prolyl endopeptidase (PEP) and thiocyanate oligopeptidase (THOP1). Alamandine can also be generated from Ang (1–7) catalyzed by AD. Ang (1–7) binds to Mas receptor (MasR) to elicit vasoprotective effects, including lowered blood pressure, reduced cardiac hypertrophy and fibrosis, thrombosis, inflammation, cell proliferation, inhibits the sympathetic nervous system and osteogenic transition of vascular smooth muscle cells (VSMCs), but promotes vasodilatation, the release of atrial natriuretic peptide, and NO production. By binding to AT2R and Mas-related G protein-coupled receptor member D (MrgDR), respectively, Ang (1–9) and alamandine exhibit cardioprotective effects, such as enhanced vasodilatation, reduced blood pressure, and improved cardiac hypertrophy and fibrosis. Illustration was created with BioRender.com.

Fig. 2

Signal transduction mechanisms of the counter-regulatory RAS and process of SARS-CoV-2 entry into the host cell. Left: Signal transduction cascades of the three principal axes of the counter-regulatory RAS in the heart, vasculature, and brain. a) ACE2-Ang (1–9)-AT2R: Stimulation of AT2R is coupled with G_i/s, leading to the activation of Src homology 2-containing protein-tyrosine phosphatase-1 (SHP1) /mitogen-activated protein kinase-phosphatase 1 (MKP1) to inhibit extracellular signal-regulated kinase 1/2 (ERK1/2). Moreover, stimulation of AT2R triggers the activation of transcription factor promyelocytic zinc finger protein (PLZF), thereby promoting the expression of ribosomal protein S6 kinase β1 (p70S6K) and PI3K regulatory subunit p85α. b) ACE2-Ang (1–7)-MasR: MasR activation stimulates SHP1 and dual specificity phosphatase (DUSP), subsequently suppressing ERK1/2 and p38. In addition, the PI3K-Akt pathway triggered by Ang (1–7)-MasR activates Na⁺/H⁺ exchanger-1 (NHE1) and calcium/calmodulin-dependent protein kinase II (CaMKII), leading to the increased secretion of atrial natriuretic peptide (ANP). The norepinephrine transporter (NET) in the central nervous system can be inhibited by the PI3K-Akt pathway. Moreover, Ang (1–7)-MasR activation can inhibit calcineurin/nuclear factor of activated T-cell (NFAT) signaling via PI3K-AKT-NO-cGMP-dependent pathway. c) ACE2-Alamandine-MrgDR: Alamandine-MrgDR activation functions through the G_i/s dependent cAMP-PKA pathway to induce NO production in the heart and vasculature. Right: The process of SARS-CoV-2 invasion of the host cell via a membrane-bound ACE2 receptor. The Spike glycoprotein (S protein) of SARS-CoV-2 binds to human ACE2 on the cell membrane through the S1 subunit containing the receptor-binding domain (RBD). A disintegrin and metalloproteinase 17 (ADAM17) mediates a proteolytic shedding of ACE2 to form sACE2 that can be released into extracellular cellular space. Viral membrane fusion with the host cell is activated upon binding through two distinct pathways: a) The intact ACE2 or its transmembrane structural domain is internalized along with the virus by clathrin-dependent endocytosis; b) In the presence of transmembrane proteins and transmembrane protease serine isoform 2 (TMPRSS2) and other co-transmembrane proteins, such as vimentin, neuropilin-1 (NRLP1), cathepsin L (CTSL), furin-like proteases (Furin), the S protein of SARS-CoV-2 is cleaved to trigger membrane fusion and cellular uptake of the virus. The host cell machinery promotes the release of the viral RNA into the cytoplasm for replication and translation. Illustration was created with BioRender.com.

Fig. 3

Hypertension pharmacological treatment in the context of the COVID-19 pandemic. SARS-CoV-2 infection-induced cytokine storm, intravascular coagulation, and multi-organ dysfunction are the leading cause of severe COVID-19. The relationship between hypertension and COVID-19 is bidirectional. Numerous observational studies have confirmed that hypertension is an independent risk factor for SARS-CoV-2 infection and a severe COVID-19 outcome. However, the effects of COVID-19 on both pre-existing and newly diagnosed hypertension are still disputable. The safety and efficacy of the first-line BP-lowering drugs, including beta-blockers, thiazide diuretics, RAS blockers (ACEIs and ARBs) and calcium channel blockers (CCB) have been confirmed in COVID-19 patients with hypertension, some of these agents even provide additional benefits for treating COVID-19, but the mechanisms underlying this protective response remain largely unknown. Pharmacological agents/strategies targeting the counter-regulatory RAS to treat hypertension are highlighted in pink rectangle (artificial agents) and green cycle (natural ligands), including a) ACE2 upregulation: all-trans retinoic acid (atRA), xanthone (XNT), diminazene aceturate (DIZE), recombinant ACE2 protein (rACE2), and the immunoglobulin fragment Fc segment infused rACE2 (rACE2-Fc) etc.; b) MasR agonists: Ang (1–7), cAng (1–7), AVE0991, CGEN-856S; c) AT2R agonists: Ang (1–9), CGP42112, Novokinin, Compound 21 (C21) etc.; d) MrgDR agonist: Alamandine, and alamandine-HPβCD. The priming of ACE2 in activity or expression may also provide protection against severe COVID-19. Illustration was created with BioRender.com.