Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

Abstract

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.

Electroacupuncture Treats Myocardial Infarction by Influencing the Regulation of Substance P in the Neurovascular to Modulate PGI2/TXA2 Metabolic Homeostasis via PI3K/AKT Pathway: A Bioinformatics-Based Multiomics and Experimental Study

“…In addition to the rupture of coronary artery plaque to form a clot that blocks the lumen of the artery, an increase in oxygen consumption by the myocardium and coronary artery spasm can also induce AMI [ 1 , 2 ]. Coronary spasms are caused by various factors, like prostacyclin (PGI2) and thromboxane A2 (TXA2) [ 3 , 4 ]. Therefore, ELISA was used to check the protein levels of PGI2 and TXA2 in the sera of the mice.…”

“…AMI causes ischemia and hypoxia in the myocardium, which can cause pain, anxiety, and changes in cardiac function and promote sympathetic nerve activity. Neuropeptides are important prognostic markers of AMI [3][4][5][6]. The release of neuropeptide Y (NPY) from nerve fibers in the myocardium reduces blood flow to the vascular tissue in the infarct area [7].…”

Circulating microRNAs as emerging regulators of COVID-19

“…Conversely, an increase in angiotensin II following ACE2 inhibition may increase disease severity 149 . Interestingly, ACE2 catalyzes the conversion of angiotensin II to angiotensin 1-7, which is an important component of signaling in the renin-angiotensin system throughout the body, and exhibits anti-inflammatory, antiremodeling, and antiproliferative properties by reducing angiotensin II levels 150 . In addition, previous studies have shown that miR-200C-3p, upregulated by NF-κB, can directly target the 3'UTR of ACE2 and downregulate the ACE2 protein level to increase Ang II and cause lung injury through the Ang II type 1 receptor 148 .…”

Alamandine alleviated heart failure and fibrosis in myocardial infarction mice

“…There is growing recognition and experimental evidence that the circulating renin–angiotensin–aldosterone system (RAAS), as a coordinated hormonal cascade, is critically important in regulating cardiovascular system under different physiological and pathological conditions [ 5 ]. As the most potent bioactive molecule involved in the classic angiotensin-converting enzyme-Angiotensin II-Angiotensin II type 1 receptor (ACE-AngII-AT1R) axis, AngII ensures the development of pathological cardiac remodeling upon myocardial infarction (MI) [ 6 ]. Ang-(1-7) is demonstrated to oppose the harmful effects of AngII/AT1R axis via binding to the Mas receptor [ 7 ].…”

“…The heptapeptide Ala-Arg-Val-Tyr-Ile-His-Pro (named as alamandine), a novel effector molecule of the RAAS protective arm, has the similar chemical structure of Ang-(1-7) with only one amino acid residue difference [12]. Alamandine (Ala) can be generated from the direct decarboxylation of Ang- (1)(2)(3)(4)(5)(6)(7) or from ACE2-mediated hydrolysis of angiotensin A [13]. Interestingly, the previous data on animals showed that Ala exerts similar antihypertrophic and hypotensive actions to Ang-(1-7) [14,15].…”