New Approaches Targeting the Renin-Angiotensin System: Inhibition of Brain Aminopeptidase A, ACE2 Ubiquitination, and Angiotensinogen

Hypertension affects one-third of the adult population and is the leading cause of premature death and disability-adjusted life years, being the world's leading risk factor for cardiovascular diseases including myocardial infarction, heart failure, stroke, and end-stage renal disease.1-3 Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled worldwide, and more than 50% of US adults taking antihypertensive medication have blood pressure > 130/ 80 mm Hg.4 This often is caused by nonadherence. Prevalence of hypertension is increasing because of the aging of populations and the obesity epidemic.5 Therefore, there is still a need for the development of new antihypertensive drugs acting on new targets, with different modes of action, to improve blood pressure control. This review discusses novel insights with regard to interference with the renin-angiotensin system (RAS), focusing on the enzymes aminopeptidase A (APA) and angiotensin-converting enzyme 2 (ACE2), as well as the substrate of renin: angiotensinogen.