A Ying-Yang Perspective on the Renin Angiotensin System in Cardiovascular Disease

The renin angiotensin systemRenin angiotensin system (RAS) plays a critical role in the regulation of the homeostatic control of arterial pressure, body fluids, and cardiovascular adjustments to metabolic needs. Angiotensin IIAngiotensin II (Ang II) is considered to be the main effector molecule of the RASRenin angiotensin system contributing to the adverse cardiac, vascular, and renal organ remodeling in the development and progression of the cardiovascular diseaseCardiovascular disease (CVD) through the activation of specific Ang II type 1 receptorAngiotensin-II type 1 (AT1) receptor (AT1R). The endocrine action of circulating Ang IIAngiotensin II in blood pressure regulation have been extensively documented. The biochemical pathways leading to the generation of the biologically active angiotensins result from the metabolic processing of angiotensinogen, a 425 amino acid protein synthetized primarily by the liver. According to the classical pathway, Ang II is generated by sequential cleavage of angiotensinogen to angiotensin IAngiotensin I (Ang I) by renal reninRenin. Ang IAngiotensin I is then cleaved into Ang IIAngiotensin II primarily by angiotensin converting enzyme (ACE) in circulation and by chymaseChymase in the tissues. The complexity of biochemical cascade leading to the production of Ang II, the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)], and other biologically active peptides has now been expanded by the identification of shorter forms of the angiotensinogen substrate that upstream of Ang IAngiotensin I are processed by non-renin dependent mechanisms. This chapter will detail the biochemical physiology of angiotensin-(1-12)Angiotensin (1-12) [Ang-(1-12)] and its function as an endogenous source for Ang IIAngiotensin II generation. Collectively, the discovery of Ang-(1-12) offers an opportunity to unravel how intracellular synthesis of angiotensins proceeds through different biochemical mechanisms.