Angiotensin (1-7)
Cardiovascular / Anti-InflammatoryAlso known as: Ang(1-7), A(1-7), Angiotensin 1-7
Mechanism
The "good" angiotensin — a natural peptide that opposes the harmful effects of Angiotensin II (the one that raises blood pressure and causes inflammation). It is produced by the enzyme ACE2, which became famous as the entry point for COVID-19. Angiotensin (1-7) dilates blood vessels, reduces inflammation, and protects the heart, lungs, and kidneys. Research interest exploded after the pandemic because COVID-19 disrupts this protective pathway.
Technical detail
Heptapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro) generated primarily by ACE2-mediated cleavage of Angiotensin II (removing the C-terminal Phe). Signals through the Mas receptor (MasR), a G-protein-coupled receptor, activating phospholipase A2, increasing NO and prostaglandin I2 production, and stimulating Akt phosphorylation. Opposes Angiotensin II/AT1R signaling: vasodilation (vs. vasoconstriction), anti-inflammatory (vs. pro-inflammatory), anti-fibrotic (via SMAD pathway inhibition vs. TGF-beta activation), anti-proliferative, and anti-thrombotic. SARS-CoV-2 binding to ACE2 reduces its expression, depleting Ang(1-7) and shifting the RAAS balance toward Angiotensin II — contributing to COVID-19 lung injury, inflammation, and coagulopathy. Therapeutic Ang(1-7) administration in clinical trials for COVID-19, pulmonary hypertension, and heart failure.
Effects
CARDIOVASCULAR SYSTEM: Counter-regulatory arm of the renin-angiotensin-aldosterone system (RAAS) — Ang-(1-7) opposes virtually every effect of Angiotensin II via the Mas receptor (MasR). Vasodilation via endothelial NO release and prostaglandin I2 production [RCT, animal]. Antihypertensive — reduces systemic blood pressure in multiple hypertensive models [animal, early clinical]. Anti-fibrotic — inhibits cardiac fibroblast proliferation and collagen deposition, reducing cardiac remodeling after MI [animal]. Anti-hypertrophic — prevents pathological left ventricular hypertrophy [animal]. Anti-arrhythmic — reduces susceptibility to atrial and ventricular arrhythmias [animal]. Improves endothelial function and reduces atherosclerotic plaque progression [animal]. PULMONARY SYSTEM: Potent anti-fibrotic and anti-inflammatory in lung tissue — reduces bleomycin-induced pulmonary fibrosis [animal]. Protective in acute lung injury/ARDS models — the ACE2/Ang-(1-7)/Mas axis is critical (ACE2 converts Ang II to Ang-(1-7)) [animal]. COVID-19 connection: SARS-CoV-2 uses ACE2 for cell entry, downregulating ACE2 and reducing Ang-(1-7) production — this imbalance (excess Ang II, deficient Ang-(1-7)) contributes to COVID-19 lung injury and cytokine storm [clinical observation, mechanistic studies]. RENAL SYSTEM: Nephroprotective — reduces proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis in diabetic nephropathy models [animal]. Natriuretic and diuretic effects opposing Ang II-mediated sodium retention [animal]. METABOLIC: Improves insulin sensitivity and glucose uptake in skeletal muscle [animal]. Anti-diabetic effects — reduces pancreatic β-cell dysfunction [animal]. Reduces hepatic steatosis and liver fibrosis [animal]. NEUROLOGICAL: Neuroprotective — reduces neuroinflammation and cerebral ischemia injury [animal]. Improves cognitive function in Alzheimer's models via anti-inflammatory and anti-amyloidogenic effects [animal]. ANTI-INFLAMMATORY: Broadly anti-inflammatory — suppresses NF-κB, reduces TNF-α, IL-6, IL-1β, and promotes anti-inflammatory IL-10 [in vitro, animal].
Practitioner Guide
ADMINISTRATION: Ang-(1-7) is under active pharmaceutical development but NOT yet approved for any indication. Experimental routes: subcutaneous injection, oral (cyclodextrin-encapsulated formulations — TXA127/Constant Therapeutics), intranasal, and inhaled (for pulmonary indications). TXA127 is an oral formulation that has reached clinical trials. DOSING (EXPERIMENTAL): Clinical trials have used TXA127 at 0.5-1.0 mg/kg/day orally. Subcutaneous dosing in research: 100-1000 mcg/kg/day. No established clinical dosing outside of trials. PHARMACOKINETICS: Very short half-life in plasma (seconds to minutes) — rapidly degraded by ACE, neprilysin, and other peptidases. This is the major therapeutic challenge. Oral bioavailability near zero without formulation technology (cyclodextrin inclusion complexes, nanoparticles). SUPPORTING ENDOGENOUS ANG-(1-7): Since direct supplementation is impractical outside trials, clinicians can support the ACE2/Ang-(1-7) axis indirectly: ACE inhibitors and ARBs upregulate ACE2 and increase Ang-(1-7) levels (one mechanism of their benefit beyond Ang II blockade). Exercise increases ACE2 expression and Ang-(1-7) production. Dietary strategies: omega-3 fatty acids, polyphenols (resveratrol), and caloric restriction all upregulate ACE2 in animal models. STACKING/SYNERGY: Conceptually synergistic with ACE inhibitors/ARBs (they increase substrate for ACE2 → Ang-(1-7) conversion), antioxidants (reduce oxidative stress that impairs Mas receptor signaling), and anti-inflammatory agents. CLINICAL RELEVANCE: Understanding Ang-(1-7) helps explain why ACE inhibitors and ARBs work — they don't just block Ang II, they shift the balance toward Ang-(1-7). Also explains the cardiovascular benefits of exercise beyond the obvious. COVID-19 CONTEXT: The ACE2/Ang-(1-7) axis is why ACE inhibitors were NOT harmful in COVID-19 (they upregulate ACE2, which is protective via Ang-(1-7), despite ACE2 being the viral receptor). This was confirmed by multiple large RCTs showing no harm from continuing ACE inhibitors during COVID-19. MONITORING: Research settings monitor Ang-(1-7)/Ang II ratio as a biomarker of RAAS balance — not clinically available.
Research Summary
TIER 1: RCTs of TXA127 (oral Ang-(1-7)) in hematopoietic stem cell transplant patients (reduced severe thrombocytopenia — Phase II completed). RCTs confirming safety of continuing ACE inhibitors in COVID-19 (BRACE-CORONA, REPLACE-COVID — indirect validation of ACE2/Ang-(1-7) axis). Early-phase clinical trials in pulmonary arterial hypertension, COVID-19 ARDS, and diabetic kidney disease. TIER 2: Extensive systematic reviews of Ang-(1-7) cardiovascular effects (Santos et al., 2018 — comprehensive). Meta-analyses of ACE2/Ang-(1-7) in COVID-19 pathophysiology. Reviews of renal and metabolic protective effects. Hundreds of animal studies across virtually every organ system. TIER 3: Case reports of compassionate-use Ang-(1-7) in severe COVID-19 ARDS. Practitioner observations on ACE inhibitor/ARB effects on the Ang-(1-7) axis. International data from Brazilian cardiovascular research programs (Santos lab — pioneers of the field). KEY FINDINGS: Ang-(1-7) is one of the most validated cardiovascular peptides in preclinical research — thousands of studies across decades. The ACE2/Ang-(1-7)/Mas axis is firmly established as the counter-regulatory arm of RAAS. COVID-19 massively accelerated translational interest. The therapeutic challenge is delivery (short half-life), but TXA127 and inhaled formulations are advancing. GAPS: Limited Phase III data for any indication. Optimal dosing in humans not established for most conditions. Long-term safety of exogenous Ang-(1-7) unknown. Unclear if exogenous supplementation can fully replicate the paracrine effects of endogenous production. ACTIVE TRIALS: TXA127 in pulmonary arterial hypertension (Phase II), COVID-19 ARDS (multiple trials), diabetic kidney disease, muscular dystrophy (Phase II), and post-bone marrow transplant recovery. Inhaled Ang-(1-7) for pulmonary fibrosis (early phase).