Angiotensin (1-7) Research Overview

Background: The Counter-Regulatory RAS Axis

The renin-angiotensin system (RAS) is a hormonal cascade governing blood pressure, fluid balance, and tissue remodelling — one of the most studied and pharmacologically targeted systems in medicine. For decades, the RAS was understood as a linear pathway: renin cleaves angiotensinogen to angiotensin I, ACE (angiotensin-converting enzyme) converts angiotensin I to the active angiotensin II (Ang II), and Ang II acts on AT1 receptors to produce vasoconstriction, aldosterone release, inflammation, and fibrosis. ACE inhibitors and ARBs (AT1R blockers) exploit this pathway and represent two of the most prescribed drug classes globally.

A paradigm-shifting revision to this model emerged in the 2000s with characterisation of the ACE2/Ang(1-7)/Mas receptor axis — a counter-regulatory arm that directly opposes Ang II's harmful effects. ACE2 cleaves a single amino acid from Ang II to produce Ang(1-7), which binds the Mas receptor (a GPCR encoded by the proto-oncogene MAS1) and activates signalling pathways that are largely opposite to AT1R: vasodilation instead of vasoconstriction, anti-fibrotic instead of pro-fibrotic, anti-inflammatory instead of pro-inflammatory, and cardioprotective instead of cardiotoxic.

• Sequence: Asp-Arg-Val-Tyr-Ile-His-Pro (heptapeptide)
• Molecular Weight: 899.0 Da
• Generating Enzyme: ACE2 (from Ang II); also neprilysin (from Ang I)
• Primary Receptor: Mas receptor (MAS1; Gi/Gq-coupled GPCR)
• Plasma Half-life: ~30 minutes (rapidly degraded by ACE and neprilysin)
• Functional Role: Counter-regulatory arm opposing Ang II/AT1R effects

The ACE2/Ang(1-7)/Mas Axis vs Ang II/AT1R Axis

| Parameter | Ang II / AT1R Axis | Ang(1-7) / Mas Receptor Axis | | --- | --- | --- | | Vascular Effect | Vasoconstriction; ↑ BP | Vasodilation; ↓ BP via NO and PGI₂ | | Cardiac Effect | Hypertrophy; fibrosis; arrhythmia | Anti-hypertrophic; anti-fibrotic; cardioprotective | | Inflammatory Effect | Pro-inflammatory (NF-κB, ROS, cytokines) | Anti-inflammatory (NO, IL-10, anti-ROS) | | Renal Effect | Sodium retention; glomerulosclerosis | Natriuresis; anti-fibrotic; renoprotective | | Lung Effect | Acute lung injury; pulmonary fibrosis | Protects against ALI; anti-fibrotic in lung | | CNS Effect | Neuroinflammation; cognitive impairment | Neuroprotective; anti-neuroinflammatory; cognitive enhancement | | Metabolic Effect | Insulin resistance; adipogenesis | Improves insulin sensitivity; reduces adiposity |

Mas Receptor Signalling

The Mas receptor is a GPCR coupled to both Gi and Gq proteins in different cell contexts. In endothelial cells — the primary vascular locus of Ang(1-7)'s cardiovascular effects — Mas activation triggers Gi-mediated PI3K/AKT signalling that phosphorylates and activates eNOS (endothelial nitric oxide synthase), producing NO-mediated vasodilation. Simultaneously, Mas activation inhibits NADPH oxidase — reducing superoxide production that would otherwise quench NO and impair endothelial function. The net result in the vasculature is enhanced NO bioavailability, reduced oxidative stress, and improved endothelial function — mechanisms directly opposing the Ang II/AT1R-mediated effects of NADPH oxidase activation and eNOS uncoupling.

In cardiac fibroblasts, Mas receptor activation opposes the TGF-β1/Smad2/3 fibrotic signalling driven by AT1R — reducing collagen I/III synthesis and myofibroblast differentiation. This antifibrotic Mas signalling is particularly relevant to cardiac remodelling research, where the balance between the ACE/Ang II/AT1R axis and the ACE2/Ang(1-7)/Mas axis determines the degree of post-injury fibrosis and functional recovery.

Research Domains

#### Cardiovascular

Vasodilation via Mas/NO/PGI₂. Anti-cardiac hypertrophy. Anti-fibrotic in heart failure models. Cardioprotective in I/R injury. Studied in heart failure, hypertension, and post-MI remodelling research.

#### Renal Protection

Reduces glomerulosclerosis in diabetic nephropathy models. Promotes natriuresis. Reduces renal fibrosis via TGF-β suppression. Mas receptor expression in proximal tubules confirmed.

#### Anti-inflammatory

Reduces NF-κB activity. Lowers TNF-α, IL-6, MCP-1. Increases anti-inflammatory IL-10. Studied in ALI, IBD, arthritis, and neuroinflammation models across multiple organ systems.

#### Cognitive & Neurological

Improves spatial memory and learning in aged rodents. Reduces neuroinflammation. Protects hippocampal neurons in ischaemia models. ACE2/Mas expression in hippocampus and prefrontal cortex confirmed.

#### Metabolic

Improves skeletal muscle insulin sensitivity via Mas/PI3K/AKT/GLUT4. Reduces adipose inflammation. Opposes Ang II–induced insulin resistance. Studied in T2DM and metabolic syndrome models.

#### Pulmonary/COVID-19

ACE2 is the SARS-CoV-2 entry receptor — viral binding depletes ACE2 and Ang(1-7) production, shifting RAS toward pro-inflammatory Ang II dominance. Ang(1-7) supplementation studied as COVID-19 countermeasure.

COVID-19 and ACE2 Downregulation

SARS-CoV-2's relationship with Ang(1-7) is mechanistically direct and clinically significant. The virus uses ACE2 as its primary cellular entry receptor — binding ACE2 with its spike protein and internalising the ACE2-virus complex. This viral entry mechanism simultaneously depletes membrane-bound ACE2, reducing the enzyme's capacity to generate Ang(1-7) from Ang II. The result in infected lung tissue is a pathological shift in RAS balance: Ang II accumulates (because ACE2 cannot degrade it to Ang(1-7)), while Ang(1-7) levels fall — shifting the pulmonary RAS toward AT1R-mediated pro-inflammatory, pro-fibrotic, and pro-vasoconstricting effects that contribute directly to ARDS pathophysiology.

This mechanistic insight generated multiple Phase II trials evaluating exogenous Ang(1-7) (or ACE2 augmentation strategies) in COVID-19 ARDS. A Phase II RCT by Khan et al. (2017, pre-COVID) in ARDS from sepsis demonstrated that inhaled Ang(1-7) improved oxygenation indices — providing proof-of-concept for pulmonary Ang(1-7) supplementation that was subsequently tested in COVID-19 trials with promising preliminary results.

Cardiovascular Research: Heart Failure and Fibrosis

In transverse aortic constriction (TAC) models of pressure-overload heart failure — one of the standard models of cardiac remodelling — Ang(1-7) infusion significantly attenuates cardiac hypertrophy, reduces interstitial fibrosis (as measured by Masson's trichrome and hydroxyproline content), and preserves ejection fraction compared to vehicle-treated TAC animals. These effects are Mas receptor-dependent: they are abolished in Mas knockout mice and by the Mas antagonist A779. The antifibrotic mechanism involves direct suppression of TGF-β1-mediated Smad2/3 phosphorylation in cardiac fibroblasts — the same pathway that ACE inhibitors and ARBs partially target through Ang II reduction.

Formulation Challenge: Stability and Delivery > Ang(1-7)'s primary pharmacological limitation is its short plasma half-life (~30 minutes) due to rapid cleavage by ACE (converting it back to Ang(1-5), inactive) and neprilysin. Research strategies to overcome this include: cyclodextrin inclusion complexes for oral delivery, inhaled formulations for pulmonary delivery (tested in ARDS trials), and engineered analogues with ACE resistance (e.g., AVE0991 — a non-peptide Mas agonist; cyclic Ang(1-7) analogues with disulfide bridges). Each approach represents an active pharmaceutical development strategy building on Ang(1-7)'s established biology.

Cognitive Research: The Brain RAS

The brain has a local, independent RAS — including local ACE2 and Mas receptor expression in the hippocampus, prefrontal cortex, and brainstem — that operates separately from the systemic RAS. Ang(1-7) produced locally in hippocampal neurons acts on Mas receptors to exert neuroprotective and pro-cognitive effects. In aged rodents with elevated brain Ang II activity and reduced ACE2/Ang(1-7) signalling, Ang(1-7) administration (central or peripheral, given its ability to cross the blood-brain barrier to some degree) improves Morris water maze performance, reduces hippocampal neuroinflammation, and increases BDNF expression — a neurotrophic convergence with other neuroprotective peptides studied in this context.

References

1. Santos RA, et al. "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas." *Proc Natl Acad Sci USA*. 2003;100(14):8258–8263.
2. Ferrario CM, et al. "Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2." *Circulation*. 2005;111(20):2605–2610.
3. Iusuf D, et al. "Angiotensin-(1-7): pharmacological properties and pharmacokinetics." *Curr Drug Targets Cardiovasc Haematol Disord*. 2008;8(3):185–193.
4. Hoffmann M, et al. "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor." *Cell*. 2020;181(2):271–280.
5. Becker LK, et al. "Intranasal administration of angiotensin-(1-7) reduced cognitive impairment in aged rats." *Physiol Behav*. 2007;92(3):442–450.
6. Khan A, et al. "A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome." *Crit Care*. 2017;21(1):234.