The RAAS Goodfellas in Cardiovascular System

Abstract

In the last two decades, the study of the renin–angiotensin–aldosterone system (RAAS) has revealed a counterregulatory protective axis. This protective arm is characterized by ACE2/Ang 1-7/MasR and Ang 1-9 that largely counteracts the classic arm of the RAAS mediated by ACE/Ang II/AT1R/aldosterone and plays an important role in the prevention of inflammation, oxidative stress, hypertension, and cardiovascular remodeling. A growing body of evidence suggests that enhancement of this counterregulatory arm of RAAS represents an important therapeutic approach to facing cardiovascular comorbidities. In this review, we provide an overview of the beneficial effects of ACE2, Ang 1-7/MasR, and Ang 1-9 in the context of oxidative stress, vascular dysfunction, and organ damage.

Possible Molecular Mechanisms of Hypertension Induced by Sleep Apnea Syndrome/Intermittent Hypoxia

“…The RAS has been shown to elevate ROS levels and plays a role in the development of hypertension caused by IH and SAS [80][81][82][83]. Angiotensin II (ANG II), the primary hormone responsible for the actions of RAS, affects both the peripheral and central systems, which can increase sympathetic activity and play a role in the development of hypertension [84].…”

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“…It is well known that Ang II can bind two different receptors, AT1R and AT2R, the former being responsible for the deleterious effects of the renin-angiotensin system (RAS) and the latter mediating opposite effects. In addition, Ang 1-7 binds the Mas receptor exerting anti-inflammatory, antithrombotic, antiproliferative, and vasodilatory effects, and the ACE2-Ang 1-7 pathway is considered the counter-regulatory arm of RAS [5].…”

“…Gitelman and Bartter Syndromes (GS/BS) are two rare genetic tubulopathies characterized by metabolic alkalosis, hypokalemia (hypomagnesemia in GS), hyperactivation of RAS, and high Ang II and aldosterone level, yet normo/hypotension [9,10] and activation of the RAS counter-regulatory arm with increased ACE2 and Ang 1-7 levels, resulting in antiatherosclerotic, antiproliferative, and antifibrotic effects [5,11]. The Ang II-AT1R signaling pathway is indeed blunted in these patients, as they show a downregulation of the RhoA-Rho kinase (ROCK) pathway due to a higher expression of the Regulator of G-protein Signaling 2 that regulates the Ang II G protein coupled receptor signaling.…”

“…The Ang II-AT1R signaling pathway is indeed blunted in these patients, as they show a downregulation of the RhoA-Rho kinase (ROCK) pathway due to a higher expression of the Regulator of G-protein Signaling 2 that regulates the Ang II G protein coupled receptor signaling. The reduced activation of ROCK in GS/BS accounts for their increased vasodilation, antioxidant defenses, and antiatherogenesis, despite the increased levels of Ang II [5,11].…”

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“…RAAS inhibitors include angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARBs), aldosterone antagonists, and direct renin inhibitors ( 20 ). Recent studies have found that RAAS inhibitors significantly slow the progression of a wide range of diseases, including hypertension, myocardial remodeling after acute myocardial infarction, acute and chronic heart failure, and renal insufficiency, improving the prognosis of patients ( 21 , 22 ). RAAS inhibitors dilate the glomerular outgoing and incoming small arteries to different degrees, and reduce the glomerular intraglomerular pressure leading to a decrease in urinary protein ( 23 ).…”