Counter-regulatory renin–angiotensin system in cardiovascular disease

The renin–angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II — initially thought to be biologically inactive — have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin–angiotensin system consists of angiotensin 1–7, angiotensin 1–9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT 2 R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin–angiotensin system. This counter-regulatory renin–angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin–angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease. The non-canonical axis of the renin–angiotensin system (RAS) has an important role in cardiovascular physiology and disease. In this Review, Ocaranza and colleagues discuss the interplay between components of the counter-regulatory RAS and the therapeutic potential of targeting this system to treat cardiovascular disease. Key points Chronic activation of the renin–angiotensin system (RAS) promotes cardiovascular damage, an effect that is antagonized by components of the counter-regulatory RAS. Components of the counter-regulatory RAS, including angiotensin 1–7, angiotensin 1–9, alamandine and their receptors have been found to be protective in multiple cardiovascular diseases, such as hypertension and heart failure. Numerous preclinical studies have demonstrated the beneficial effects of the counter-regulatory RAS, but clinical trials confirming these observations are still scarce. The challenges in quantitating angiotensin 1–7, angiotensin 1–9 and alamandine associated with their short plasma half-life and similarity in their molecular structures must be overcome before these peptides can be evaluated in the clinical setting.