Angiotensin (1-7)

Angiotensin (1-7) [Ang(1-7)] is a seven-amino acid peptide produced primarily by the action of angiotensin-converting enzyme 2 (ACE2) on angiotensin II. It represents the protective arm of the renin-angiotensin system (RAS), counterbalancing the vasoconstrictive, pro-inflammatory, and pro-fibrotic effects of angiotensin II acting through the AT1 receptor. The concept of a protective RAS axis, centered on the ACE2/Ang(1-7)/Mas receptor pathway, has fundamentally expanded the understanding of cardiovascular regulation.

Ang(1-7) acts primarily through the Mas receptor, a G-protein coupled receptor, to produce effects that are largely opposite to those of angiotensin II at AT1 receptors. These include vasodilation, anti-proliferative effects on vascular smooth muscle, anti-fibrotic actions, anti-inflammatory properties, and anti-thrombotic effects. In the heart, Ang(1-7) has been shown to reduce cardiac hypertrophy and fibrosis, improve endothelial function, and provide protection against ischemia-reperfusion injury.

The ACE2/Ang(1-7)/Mas axis gained enormous public attention during the COVID-19 pandemic because ACE2 serves as the entry receptor for SARS-CoV-2. Viral binding to and downregulation of ACE2 was hypothesized to reduce Ang(1-7) production, potentially shifting the RAS balance toward the harmful angiotensin II/AT1 receptor axis. This imbalance was proposed as a contributing mechanism to the severe cardiovascular and pulmonary pathology observed in COVID-19.

Therapeutic development of Ang(1-7) has explored its potential in hypertension, heart failure, diabetic nephropathy, pulmonary hypertension, and stroke. Challenges include the peptide's short half-life and the need for parenteral administration. Cyclic Ang(1-7) analogs, oral formulations using inclusion complexes (e.g., with hydroxypropyl-β-cyclodextrin), and nonpeptide Mas receptor agonists are being developed to overcome these limitations.