Renin-Angiotensin-Aldosterone System in Heart Failure: Focus on Nonclassical Angiotensin Pathways as Novel Upstream Targets Regulating Aldosterone

Abstract

Aldosterone plays an important role in the regulation of blood pressure, body fluid, and electrolyte homeostasis. Overactivation of aldosterone/ mineralocorticoid receptor (MR) pathway leads to hypertension, atherosclerosis, vascular damage, heart failure, and chronic kidney disease and is involved in many other diseases associated with endothelial dysfunction, inflammation, fibrosis, and metabolic disorders. Aldosterone is a final product of the renin-angiotensin-aldosterone system (RAAS), and its production is activated by angiotensin II, while angiotensin-(1-7) negatively regulates angiotensin II-mediated aldosterone production and in some experimental models inhibits aldosterone-induced damage in target tissues. In fact, the aldosterone/mineralocorticoid receptor-dependent pathway is regulated upstream by at least two major axes of RAAS: classical axis (ACE/Ang II) and nonclassical axis (ACE2/Ang-(1-7)). The relative balance between these two axes determines aldosterone production and activity. To better understand the regulation of aldosterone activity in physiology and diseases, it is important to analyze the role of aldosterone/mineralocorticoid receptor-dependent pathways in the context of upstream angiotensin pathways as some of the recently described mechanisms of RAAS represent possible novel upstream targets to inhibit aldosterone/mineralocorticoid receptor-dependent responses. In this review, we highlight the complexity of angiotensin pathways focusing on their role in various tissues in heart failure, with particular emphasis on nonclassical pathways including protective ACE2/Ang-(1-7) axis and detrimental Ang-(1-12)/chymase/Ang II axis.

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

“…Chymase is a major player in cardiac remodeling, characterizing heart failure, probably via Ang-1–12/chymase/Ang II or Ang I/chymase/Ang II trails ( 68 ). Furthermore, chymase-mediated generation of Ang II from Ang-(1–12) was suggested to be involved in the inotropic, contractile, and proarrhythmic effects of Ang II in experimental and clinical heart failure ( 69 , 70 ). Indeed, chronic inhibition of chymase was found to prevent cardiac fibrosis and improved diastolic dysfunction in a model of progressive heart failure in dogs ( 71 ).…”