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 (AT₂R), 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.