Role of the RAAS in mediating the pathophysiology of COVID-19

Abstract

The renin-angiotensin-aldosterone system (RAAS) holds a position of paramount importance as enzymatic and endocrine homeostatic regulator concerning the water-electrolyte and acid-base balance. Nevertheless, its intricacy is influenced by the presence of various complementary angiotensins and their specific receptors, thereby modifying the primary RAAS actions. Angiotensin-converting enzyme 2 (ACE2) acts as a surface receptor for SARS-CoV-2, establishing an essential connection between RAAS and COVID-19 infection. Despite the recurring exploration of the RAAS impact on the trajectory of COVID-19 along with the successful resolution of many inquiries, its complete role in the genesis of delayed consequences encompassing long COVID and cardiovascular thrombotic outcomes during the post-COVID phase as well as post-vaccination, remains not fully comprehended. Particularly noteworthy is the involvement of the RAAS in the molecular mechanisms underpinning procoagulant processes throughout COVID-19. These processes significantly contribute to the pathogenesis of organ complications as well as determine clinical outcomes and are discussed in this manuscript.

Keywords: ADAM17; Angiotensin; COVID-19; Coagulation; RAAS; SARS-CoV-2.

Fig. 1

AT1R, ADAM17 and ACE2 interaction. (1) Ang II binds to AT1R, leading to the induction of ADAM17; (2) ADAM17 cleaves ACE2, resulting in the release of sACE2; (3) In presence of ARB, such as losartan, Ang II cannot bind to its receptor and the induction of ADAM17 is stopped. (4) Zn2 + chelating agents block ADAM17 metalloproteinase and inhibit ACE2 shedding. This results in a decrease in circulating sACE2 and increase in mACE2. Ang II angiotensin II, AT1R angiotensin II receptor type 1, ACE2 angiotensin converting enzyme 2, sACE2 soluble angiotensin converting enzyme 2, ARB angiotensin II receptor blocker, ADAM17 A disintegrin and metalloproteinase 17

Fig. 2

Positive effects of administration of ACEIs, ARBs and rhsACE2. (1) ACE2 breaks down Ang II into Ang 1–7; (2) Ang 1–7 binds to the MasR, activating it and resulting in vasodilation, anti-inflammatory and antioxidant effects; (3) This process can be stimulated by the administration of rhsACE2 which inhibits the depletion of ACE2, or ACEIs/ARBs which block ACE/Ang II/AT1R pathway, resulting in increased ACE2 activation. Ang II angiotensin II, ACE2 angiotensin-converting enzyme 2, Ang 1–7 angiotensin 1–7, ACEIs angiotensin-converting-enzyme inhibitors, ARBs angiotensin II receptor blockers, MasR Mas receptor

Fig. 3

Mechanism of hypercoagulation in SARS-CoV-2 infection. (1) Hyperinflammation caused by SARS-Cov-2 infection leads to the production of C3a and C5a and the upregulation of PMNs; (2) Endothelial injury, PMNs, C3a and C5a increase TF exposure to blood coagulation factors; (3) Pro-inflammatory cytokines released in hyperinflammation inhibit TFPI; (4) SARS-CoV-2 infection leads to the release of neutrophil extracellular traps, which activate FXII. FXII is also activated by endothelial injury and PMNs; (5) Stimulation of both intrinsic coagulation pathway through FXII activation and extrinsic coagulation pathway through TF exposure results in hypercoagulation and prothrombotic state. PMN polymorphonuclear leukocytes, TFPI tissue factor pathway inhibitor, FXII coagulation factor XII, C3a complement component 3a, C5a complement component 5a

Fig. 4

Mechanism of hypo-fibrinolysis in SARS-CoV-2 infection. (1) Lung damage in the course of the SARS-Cov-2 infection results in reduced ACE2 expression, leading to increased Ang II production by ACE; (2) Ang II induces expression of PAI-1 and the breakdown of bradykinin into inactive peptides. tPA production decreases due to bradykinin breakdown; (3) Excessive PAI-1 production further suppresses tPA activity, resulting in hypo-fibrinolysis and prothrombotic state; (4) Administration of ACEi has been suggested to decrease PAI-1 and increase tPA Ang I angiotensin I, Ang II angiotensin II, Ang (1–7) angiotensin (1–7), Ang (1–9) angiotensin (1–9), ACE angiotensin-converting enzyme, ACE2 angiotensin converting enzyme 2, tPA tissue plasminogen activator, ACEi angiotensin-converting-enzyme inhibitors, PAI-1 plasminogen activator inhibitor-1