Angiotensin (1-7)

Ang-(1-7) binds MAS with high affinity, activating Gi/Gq signaling to increase nitric oxide (NO) production via eNOS activation, reduce NADPH oxidase-derived reactive oxygen species, and decrease NF-kB-driven inflammatory transcription. The net effect is vasodilation, anti-thrombotic activity (reduced platelet aggregation), and anti-fibrotic signaling. MAS is expressed in the heart, kidney, brain, testis, and vasculature. In the kidney, MAS activation promotes natriuresis and reduces tubular sodium reabsorption, contributing to blood pressure lowering. In the brain, MAS is expressed in hippocampal neurons where Ang-(1-7) promotes memory consolidation.

In heart failure, hypertension, and chronic kidney disease, the ACE/Ang II/AT1 axis is overactivated while the ACE2/Ang-(1-7)/MAS axis is suppressed, contributing to the progressive tissue damage these conditions cause. ACE inhibitors and ARBs partially restore balance by reducing Ang II levels, but direct Ang-(1-7) augmentation offers more targeted activation of the protective axis. In pulmonary fibrosis, the ACE2/Ang-(1-7) axis reduces TGF-beta-driven collagen deposition in lung fibroblasts, the central mechanism of fibrotic progression. This anti-fibrotic action spans cardiac, renal, and hepatic fibrosis as well.

SARS-CoV-2 spike protein binds ACE2 as its cellular entry receptor. After endosomal uptake, ACE2 is internalized and degraded, reducing surface ACE2 expression and consequently impairing Ang II-to-Ang-(1-7) conversion. This shifts the RAS balance toward the harmful ACE/Ang II/AT1 arm, contributing to COVID-19-associated vasoconstriction, inflammation, and fibrosis in lung, heart, and kidney. Exogenous Ang-(1-7) or ACE2 administration has been proposed as a countermeasure and was tested in clinical trials during the pandemic, with mixed results in acute severe disease but some positive signals in post-COVID recovery.

Multiple Phase II trials of Ang-(1-7) infusion in heart failure patients showed significant improvements in cardiac output, reductions in pulmonary wedge pressure, and improvements in natriuretic peptide levels. TXA127 (an Ang-(1-7) formulation) showed positive Phase II results for cancer therapy-associated anemia and neutropenia. The RACE trial (Ramos et al) in Brazilian patients with heart failure showed improved exercise capacity and reduced BNP with Ang-(1-7) infusion.

Ang-(1-7) preserves skeletal muscle mass in cancer cachexia models by activating MAS receptors on muscle cells, increasing Akt/mTOR signaling and reducing atrophy-promoting FoxO and atrogin-1 expression. Phase II data from University of Virginia showed Ang-(1-7) significantly prevented lean mass loss and maintained physical function in cancer patients undergoing chemotherapy, a remarkable result for a non-anabolic non-GH mechanism.

Ang-(1-7) improves insulin sensitivity by increasing glucose uptake in skeletal muscle via MAS/NO/PI3K signaling and reducing adipose tissue inflammation. In diabetic nephropathy models, Ang-(1-7) reduces glomerular filtration decline, proteinuria, and tubular fibrosis. The combination of insulin sensitization and renal protection makes Ang-(1-7) particularly relevant in cardiometabolic disease.