The renin–angiotensin system biomolecular cascade: a 2022 update of newer insights and concepts

A large body of evidence implicates the renin–angiotensin system in the pathogenesis of cardiovascular disease. However, not everyone understands that the magnitude of the risk reduction achieved in clinical trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is only a fraction of the residual risk for cardiovascular events and death. This paper addresses limitations of current therapeutic approaches based on renin–angiotensin system blockade for hypertension and cardiovascular disease by illustrating the complex biochemical physiology and mechanism of classical and alternate angiotensin peptide formation. Emerging evidence of alternate mechanisms that bypass both renin and angiotensin-converting enzyme to produce the angiotensins in tissues and cells is not currently universally recognized. Currently available treatment would benefit from further insights to help fully meet the aims of patient care, and the challenge is to delve more deeply into the renin–angiotensin system cascade, with the aim of enhancing therapeutics for renin–angiotensin system inhibition. This article provides a reappraisal of the renin–angiotensin–aldosterone cascade, highlighting newly elucidated intermediary components and interplay, and their consequent implications and relevance for understanding the long-term contribution of angiotensin II in cardiovascular diseases and their therapy.