The Role of Renin-Angiotensin-Aldosterone System in the Heart and Lung: Focus on COVID-19

Abstract

The renin-angiotensin-aldosterone system (RAAS) firstly considered as a cardiovascular circulating hormonal system, it is now accepted as a local tissue system that works synergistically or independently with the circulating one. Evidence states that tissue RAAS locally generates mediators with regulatory homeostatic functions, thus contributing, at some extent, to organ dysfunction or disease. Specifically, RAAS can be divided into the traditional RAAS pathway (or classic RAAS) mediated by angiotensin II (AII), and the non-classic RAAS pathway mediated by angiotensin 1–7. Both pathways operate in the heart and lung. In the heart, the classic RAAS plays a role in both hemodynamics and tissue remodeling associated with cardiomyocyte and endothelial dysfunction, leading to progressive functional impairment. Moreover, the local classic RAAS may predispose the onset of atrial fibrillation through different biological mechanisms involving inflammation, accumulation of epicardial adipose tissue, and electrical cardiac remodeling. In the lung, the classic RAAS regulates cell proliferation, immune-inflammatory response, hypoxia, and angiogenesis, contributing to lung injury and different pulmonary diseases (including COVID-19). Instead, the local non-classic RAAS counteracts the classic RAAS effects exerting a protective action on both heart and lung. Moreover, the non-classic RAAS, through the angiotensin-converting enzyme 2 (ACE2), mediates the entry of the etiological agent of COVID-19 (SARS-CoV-2) into cells. This may cause a reduction in ACE2 and an imbalance between angiotensins in favor of AII that may be responsible for the lung and heart damage. Drugs blocking the classic RAAS (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) are well known to exert a cardiovascular benefit. They are recently under evaluation for COVID-19 for their ability to block AII-induced lung injury altogether with drugs stimulating the non-classic RAAS. Herein, we discuss the available evidence on the role of RAAS in the heart and lung, summarizing all clinical data related to the use of drugs acting either by blocking the classic RAAS or stimulating the non-classic RAAS.

Alamandine: Potential Protective Effects in SARS-CoV-2 Patients

“…Cardiac hypertrophy and fibrosis are common effects of this process, and they often lead to adverse ventricular remodeling [ 18 ]. Ang II is also commonly responsible for inflammatory processes and alterations in the electrophysiological properties of the heart [ 19 ].…”

“…The activity of various proinflammatory transcription nuclear factors (e.g., nuclear factor-kappaB (NF- κ B)) is also increased [ 21 ]. Additionally, ATI receptors cause the release of proinflammatory cytokines, such as tumor necrosis factor- α (TNF- α ) and interleukin-6 (IL-6) [ 19 ].…”

“…Moreover, empirical studies have not confirmed the connections between ARB and ACE-inhibitor use and COVID-19 diagnosis, hospital admission due to COVID-19, and COVID-19 severity [ 19 , 24 ].…”

“…At the same time, Ang II is not effectively converted into Ang-(1-7) or alamandine. Because of this, the levels of proinflammatory Ang II are increased, while the levels of anti-inflammatory Ang-(1-7) and alamandine are reduced [ 19 ].…”

Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells

“…SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface (Hoffmann et al, 2020). However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system (Mascolo et al, 2021). Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-convertingenzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells (Tikellis et al, 2003;Ferrario et al, 2005a;Ferrario et al, 2005b;Ocaranza et al, 2006;Yang et al, 2013;Zhang et al, 2014), fueling debate early in the COVID-19 pandemic about how these widely used medications might modulate SARS-CoV-2 infectivity and the risk of In some animal studies ARBs and ACEIs were observed to increase ACE2 expression in some tissues (Tikellis et al, 2003;Ferrario et al, 2005a;Ferrario et al, 2005b;Ocaranza et al, 2006;Yang et al, 2013;Zhang et al, 2014), but the impact of these drugs on ACE2 expression in humans is mixed , and ACE2 was found to be protective against pulmonary disease from SARS-CoV in mice (Altman et al, 2017).…”