Angiotensin 1-9

Ang 1-9 activates the Mas receptor and AT2R with distinct selectivity compared to Ang 1-7. AT2R couples through Gi and activates bradykinin/NO signaling cascades, producing vasodilation and anti-fibrotic responses. Mas receptor activation stimulates eNOS-derived NO production via PI3K/Akt phosphorylation. Both receptor pathways oppose AT1R-mediated effects of angiotensin II, providing functional counter-regulation within the RAS.

In cardiomyocytes, Ang 1-9 reduces pathological hypertrophy induced by angiotensin II or phenylephrine by blocking MAPK and calcineurin/NFAT signaling. It activates anti-apoptotic pathways (PI3K/Akt/Bcl-2) and reduces reactive oxygen species in cardiac tissue. In rat models of hypertension and heart failure, Ang 1-9 administration reduces left ventricular mass, fibrosis, and improves diastolic function. These effects persist even when equivalent blood pressure reduction is achieved by other means, indicating blood pressure-independent cardioprotection.

ACE2 is the primary enzyme generating both Ang 1-9 (from Ang I) and Ang 1-7 (from Ang II). SARS-CoV-2 uses ACE2 as its cellular entry receptor and downregulates ACE2 surface expression following binding, impairing the protective ACE2 arm of the RAS. This leads to elevated Ang II (harmful) and reduced Ang 1-7/Ang 1-9 (protective), contributing to COVID-19 pathology including cardiac injury, endothelial dysfunction, and pulmonary hypertension. Restoring ACE2 activity or providing Ang 1-7/Ang 1-9 analogues has been explored as COVID-19 adjunct therapy.

In spontaneously hypertensive rats and angiotensin II-infusion hypertension models, chronic Ang 1-9 administration reduces blood pressure, cardiac hypertrophy, and fibrosis. Effects are additive to those of ACE inhibitors and ARBs, suggesting Ang 1-9 engages receptor-independent or complementary protective pathways. AT2R knockout abolishes cardiac protective effects of Ang 1-9, confirming AT2R as a primary mediator.

In post-MI heart failure models, Ang 1-9 infusion reduces ventricular remodeling, preserves ejection fraction, and reduces infarct border zone fibrosis. Plasma Ang 1-9 levels are reduced in human heart failure patients, correlating with disease severity. These data suggest Ang 1-9 deficiency contributes to adverse post-MI remodeling and that restoration could be therapeutic.

Human and animal studies show SARS-CoV-2 infection depletes ACE2, reducing Ang 1-9 and Ang 1-7 while allowing Ang II accumulation. This RAS imbalance contributes to COVID-19-associated hypertension, myocarditis, and thrombosis. Recombinant ACE2 and Ang 1-7 supplementation studies in COVID-19 have shown promising preliminary results, indirectly supporting the therapeutic potential of restoring the Ang 1-9/1-7 axis.