Angiotensin 1-7 (Ang 1-7)

Angiotensin 1-7 (Ang(1-7)) is a biologically active 7-amino acid peptide heptapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro) that represents the counter-regulatory arm of the renin-angiotensin system (RAS). It is primarily generated by ACE2 (angiotensin-converting enzyme 2) cleavage of Angiotensin II (removing the C-terminal Phe8 residue), or by neprilysin and thimet oligopeptidase acting on Angiotensin I.

Ang(1-7) was identified as the endogenous ligand of the MAS receptor (MAS1 proto-oncogene) in a landmark 2003 Science paper by Santos et al. This discovery established the ACE2/Ang(1-7)/MAS axis as a distinct functional arm of the RAS, acting in opposition to the ACE/Ang II/AT1R axis.

**RAS balance:** - Classical axis: ACE → Angiotensin II → AT1R → vasoconstriction, aldosterone, inflammation, fibrosis, oxidative stress - Counter-regulatory axis: ACE2 → Ang(1-7) → MAS receptor → vasodilation, anti-inflammation, anti-fibrosis, natriuresis

**MAS receptor signaling:** MAS receptor is a GPCR (Gi-coupled) that, when activated by Ang(1-7): - Releases nitric oxide (vasodilation) - Activates MAPK ERK1/2 and PI3K/Akt (cardioprotection, anti-apoptosis) - Inhibits NF-κB → anti-inflammatory - Reduces TGF-β expression → anti-fibrotic

**COVID-19 relevance:** SARS-CoV-2 binds ACE2 to enter cells, effectively downregulating ACE2 expression and function. This reduces Ang(1-7) production while Ang II accumulates → exacerbated vasoconstriction, inflammation, and lung injury. The ACE2/Ang(1-7) axis is central to COVID-19 pathophysiology research, and Ang(1-7)-based therapies (TXA127, recombinant ACE2) are being studied as potential treatments for severe COVID-19-associated respiratory failure.