ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension

Abstract

The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology

“…Collectively these data provide an explanation for the lower incidence of cardiac disease in females. Previous studies show that Ang II associated signaling through the AT1 receptor is primarily responsible for pathogenic effects that can be counterbalanced by AT2R signaling (Habashi et al 2011; Mendoza-Torres et al 2015). Further, in MFS, RAS with losartan blockade but not with the ACE inhibitor enalapril resulted in decreased MMPs in the aorta and improved cardiac function (Habashi et al 2011).…”

The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice

“…36 The effect of Ang-(1-7) has been demonstrated in cardiovascular pathologies such as cardiac remodeling, fibrosis, hypertension, and endothelial dysfunction. 36,38 In the case of plasma glucose handling, target tissues evidence beneficial effects of Ang-(1-7), including in skeletal muscle. 35 Furthermore, several kidney conditions can be improved by Ang-(1-7) treatment, especially those involving fibrosis.…”

Association between circulating levels of ACE2-Ang-(1–7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients

“…Apart from ACE2, Ang-(1–7) level can also be affected by many other enzymes. It can be elevated through its formation by prolylcarboxypeptidase (PRCP), [17] NEP, prolyl endopeptidase (POP), thimet oligopeptidase (TOP), [18] and be reduced through its degeneration by aminopeptidase A. [19] In addition, there might be some unknown enzymes that could affect Ang-(1–7) levels.…”