![]() ![]() ( 7 ) In tissues with chronic inflammation, chymase also converts big endothelin 1 (ET-1) into profibrotic polypeptide ET-1. This is related to chymase being massively up-regulated in hepatocytes of regenerative nodules and α-smooth muscle-positive HSCs. In patients with decompensated cirrhosis, hepatic levels of Ang II are much more elevated, spilling into the systemic circulation. Therefore, the RAS system is already active inside the liver before the onset of cirrhosis. ( 6 ) Ang II also activates infiltrating inflammatory cells, leading to their proliferation, production of inflammatory mediators (interleukin-6 and tumor necrosis factor-α), and chemotaxis. Activated HSCs themselves express de novo ACE and AT 1Rs and also synthesize Ang II. Ang II leads to hepatic stellate cell (HSC) activation and production of profibrotic cytokines and connective tissue growth factors. ![]() ( 6 ) Although the endothelium produces Ang II through ACE, chymase produces 80% of Ang II found in tissues. In the diseased liver, hepatic levels of Ang II are already elevated in pre-cirrhosis animal models of liver fibrosis. ( 4 ) The RAS Inside the LiverĪCE, Ang II, and its angiotensin type 1 receptor (AT 1R) as well as ACE2, Ang1-7, MasRs, chymase, and neprilysin are expressed in the healthy and, especially, in the diseased liver, in which they modulate vascular tone and the development of progressive fibrosis during chronic injury. Moreover, serine endopeptidase chymase, present in liver, heart, kidney, and ubiquitous mast cells, converts angiotensin I into Ang II as angiotensin-converting enzyme (ACE) does in the endothelium. ( 5 ) Cellular zinc-metallo-endopeptidase neprilysin can generate Ang1-7 from angiotensin I but continues to metabolize Ang1-7 at the Tyr 4-Ile 5 bond to form inactive byproduct angiotensin 1-4. Ang1-7 can be transformed into heptapeptide alamandine by an aspartate decarboxylase that converts Asp 1 of Ang1-7 into Ala 1 of alamandine, which binds to Mas-related G protein-coupled receptor member D, leading to arterial vasodilatation. The nonclassical RAS extends well beyond the ACE2-Ang1-7-MasR axis. AT 1-2-4Rs, angiotensin type 1-2-4 receptors MRGD, Mas-related G protein-coupled receptor member D. The main degradative pathway of Ang II in humans is through the sequential actions of plasma aminopeptidases A and N. Classical RAS is defined as the ACE–Ang II–AT 1R axis the nonclassical RAS is composed of the ACE2–Ang1-7–MasR axis, further metabolism of Ang1-7, and the angiotensin 2-8/angiotensin 3-8 pathway. ( 4 )ĭiagram depicting pathways of synthesis and degradation of angiotensins in classical and nonclassical RAS, with respective receptors for each bioactive peptide. This leads to vasodilatation and increased natriuresis through the production of arachidonic acid and increased cell levels of cyclic GMP. ( 2, 3 ) ACE2 cleaves the Pro 7-Phe 8 bond of Ang II to form angiotensin 1-7 (Ang1-7), which binds to cell membrane G protein-coupled receptors called Mas receptors (MasRs). ACE2 N-terminal domain is the SARS-CoV-2 binding site. The major player is ACE2, a transmembrane protein with an extracellular N-terminal domain containing a monocarboxypeptidase site and a transmembrane C-terminal tail. 1) derived from angiotensin II (Ang II) and involved in the regulation of inflammation and tissue blood perfusion. The nonclassical RAS is a network of enzymes and angiotensins (Fig. ( 2, 3 ) ACE2, the viral receptor, is also an integral part of the nonclassical or tissue renin-angiotensin system (RAS). ( 1 ) This is because the cell membrane-bound metallopeptidase angiotensin-converting enzyme type 2 (ACE2), the primary entry receptor for SARS-CoV-2, is ubiquitous, leading to multiple organs being involved in COVID-19. Comorbidities, including chronic liver diseases, arterial hypertension, obesity, diabetes, cancer, and cardiovascular and pulmonary dysfunctions, worsen the prognosis of patients with COVID-19. In severe clinical cases, SARS-CoV-2 infects type II pneumocytes and leads to acute respiratory distress syndrome. To date, more than one and a half million patients have died of the illness worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus, and the syndrome it causes is named the coronavirus disease outbreak, or COVID-19, which was first diagnosed in the year 2019.
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