key: cord-0792766-au7vauwd authors: Cure, Erkan; Ilcol, Tevfik Bulent; Cumhur Cure, Medine title: Angiotensin II, III, and IV may be important in the progression of COVID-19 date: 2020-11-10 journal: J Renin Angiotensin Aldosterone Syst DOI: 10.1177/1470320320972019 sha: 58cfa9763abe50de368687f19d9b5cf4bce4a6ac doc_id: 792766 cord_uid: au7vauwd nan According to the results of a meta-analysis, ACEIs and ARBs do not adversely affect mortality rate and duration of hospital stay in patients with COVID-19. 16 The metaanalysis indicated that ACEIs have a protective effect against COVID-19, but ARBs do not. 16 However, in patients using ACEIs, Ang II formation continues through non-ACE pathways. The existence of alternative pathways for Ang II production and the increased Ang II levels even with blockage of the Ang type-1 receptor (AT1R) render the degradation steps of Ang II important. Ang II is converted to Ang III by aminopeptidase A and Ang III is converted to Ang IV by aminopeptidase N. [10] [11] [12] Ang III increases vasopressin release from the brain and aldosterone release from the kidney. 12 When Ang III binds to AT1R, it acts in a fashion similar to Ang II, causing vasoconstriction and inflammation. 17 Ang IV binds to the Ang type-4 receptor (AT4R) leading to vasodilation, natriuresis, and nitric oxide release. 10, 11 However, Ang IV causes vasoconstriction by binding to AT1R and increases the risk of thrombosis by activating the plasminogen activator inhibitor (PAI). 11 Ang IV binding to AT4R also can cause release of PAI-1 and this may lead to thrombotic events. 18 Returning to Ang II, it may cause arteriolar thrombosis by several mechanisms independent of AT1R activation. 19 The Ang type-2 receptor plays a role in the first phases of Ang II-mediated thrombosis. AT4R plays a role in the cessation phases of Ang II-mediated thrombosis. 19 Also, T lymphocytes interact with Ang II, causing proinflammatory cytokine release and activating the platelets and the coagulation cascade. T lymphocytes mediate the acceleration of microvascular thrombosis. 20 Thrombotic events are common during COVID-19 and antithrombotic therapy has been shown to reduce mortality. 21 ACEIs and ARBs have antithrombotic effects mediated by Ang 1-7. 22 These effects may be lost when the virus disrupts ACE2 function and inhibits Ang 1-7 formation. ACEIs reduce Ang 1-7 degradation through the mechanisms mentioned above and can be protective against thrombosis triggered by SARS-CoV-2. However, ACE or AT1R blockage may not prevent thrombosis in patients using ACEIs or ARBs because, even with ACE or AT1R blockage, Ang II, Ang III, and Ang IV can cause detrimental effects in patients with COVID-19. Inhibiting ACE or blocking AT1R may not eliminate the negative effects of SARS-CoV-2 infection and may not prevent thrombosis. Therefore, treatments based only on Ang II may not be sufficient in COVID-19 patients. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article. 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