Angiotensin-(1-7)

What is Angiotensin-(1-7)?

Angiotensin-(1-7) is an endogenous 7-amino-acid peptide (Asp-Arg-Val-Tyr-Ile-His-Pro) — the active heptapeptide effector of the counter-regulatory arm of the renin-angiotensin-aldosterone system (RAAS). It is generated principally by angiotensin-converting enzyme 2 (ACE2), a zinc carboxypeptidase that cleaves the C-terminal phenylalanine from the 8-residue angiotensin II to release Ang-(1-7); ACE2 was independently cloned in 2000 by Donoghue and colleagues at Millennium Pharmaceuticals and by Tipnis, Hooper, Hyman, and Turner at the University of Leeds, and its substrate preference for angiotensin II was characterized biochemically by Vickers and colleagues in 2002. A second route generates Ang-(1-7) from the 10-residue angiotensin I via neprilysin (neutral endopeptidase, NEP) and other endopeptidases, providing an ACE-independent pathway that becomes more prominent during ACE inhibition. Ang-(1-7) signals through the Mas receptor, a previously orphan G-protein-coupled receptor encoded by the proto-oncogene MAS1, identified as the functional Ang-(1-7) receptor by Santos, Simoes e Silva, Maric, Sliwa, Machado, de Buhr, Heringer-Walther, Pinheiro, Lopes, Bader, Mendes, Lemos, Campagnole-Santos, Schultheiss, Speth, and Walther in a 2003 PNAS paper. The ACE2/Ang-(1-7)/Mas axis opposes the classical ACE/Ang II/AT1 axis at essentially every level: it produces vasodilation rather than vasoconstriction, anti-fibrotic and antiproliferative rather than pro-fibrotic and pro-hypertrophic signaling, natriuresis rather than sodium retention, and anti-inflammatory rather than pro-inflammatory tone. The two arms together form a balanced regulatory system, and the relative activity of each is now understood to be a key determinant of cardiovascular, renal, and pulmonary phenotype. Ang-(1-7) drew unprecedented attention from 2020 onward because ACE2 — the enzyme that generates it from angiotensin II — is also the entry receptor for SARS-CoV-2. SARS-CoV-2 spike protein binding to ACE2 reduces functional ACE2 activity, which mechanistically would shift RAAS balance toward unopposed angiotensin II and reduce Ang-(1-7) generation, generating substantial literature on whether the ACE2/Ang-(1-7)/Mas axis is therapeutically relevant in COVID-19 lung injury and beyond. Drug development around the peptide includes TXA127 (an oral cyclodextrin-formulated Ang-(1-7) developed by Constant Therapeutics, formerly US Biotest, tested in Marfan syndrome, COVID-19, and chemotherapy-induced thrombocytopenia), TRV027 (a beta-arrestin-biased AT1 ligand that overlaps thematically), and various cyclic and modified Ang-(1-7) analogues designed to overcome the native peptide's very short plasma half-life. As of 2026, no Ang-(1-7) product has reached approval for any indication.

What Angiotensin-(1-7) Is Investigated For

Angiotensin-(1-7) sits at an unusual intersection in modern RAAS biology: it is one of the best-characterized endogenous counter-regulatory hormones in cardiovascular medicine and a heavily studied therapeutic target, yet no Ang-(1-7) product has reached approval. The mechanistic case is strong. ACE2 cleaves angiotensin II's C-terminal phenylalanine to generate Ang-(1-7), which then engages the Mas receptor to produce vasodilation (largely through endothelial NO synthase activation, established by Sampaio and colleagues in 2007), anti-fibrotic and antiproliferative effects, natriuresis, and anti-inflammatory tone. The ACE2/Ang-(1-7)/Mas axis is now recognized as the principal counter-regulatory arm balancing the classical ACE/Ang II/AT1 axis — and the comprehensive 2018 Physiological Reviews paper from Santos and colleagues laid out the case in detail. The COVID-19 era brought unusual public visibility to Ang-(1-7) biology. SARS-CoV-2 enters cells via ACE2, and Hoffmann and colleagues (Cell 2020) established that spike-protein engagement of ACE2, with TMPRSS2-mediated priming, drives viral entry. Several lines of evidence suggested that SARS-CoV-2 infection reduces functional ACE2 activity at the cell surface and shifts RAAS balance toward unopposed angiotensin II — providing the biological rationale for trials of synthetic Ang-(1-7) and AT1-biased ligands in hospitalized COVID-19 patients (Self and colleagues, JAMA 2023). Those trials did not show clinical benefit on their primary endpoints, but the mechanistic interest has persisted. The drug development story has been frustrating but instructive. TXA127, an oral cyclodextrin-formulated Ang-(1-7) preparation developed by Constant Therapeutics (formerly US Biotest), has been tested in Marfan syndrome aortic-root dilatation, chemotherapy-induced thrombocytopenia (a property described in early-phase work by Rodgers and colleagues), and COVID-19. Cyclic and modified Ang-(1-7) analogues have been pursued to overcome the native peptide's roughly 30-second plasma half-life. The honest framing is that Ang-(1-7) is not a wellness peptide — it is an endogenous-biology and drug-target topic — and the principal practical relevance to current medicine is that ACE inhibitors and ARBs both elevate Ang-(1-7) levels as part of their mechanism, contributing to the cardioprotective and renoprotective effects of those drug classes beyond simple angiotensin II suppression.

History & Discovery

The Ang-(1-7) story unfolded over four decades and is in many ways the second act of the RAAS narrative — the counter-regulatory chapter that emerged after the classical angiotensin II/ACE story was already mature. Ang-(1-7) was identified as a discrete biologically active peptide in the 1980s, when investigators including Carlos Ferrario, Mark Chappell, K. Bridget Brosnihan, and colleagues at Wake Forest University recognized that the 7-residue product of angiotensin I and angiotensin II metabolism was not simply an inactive degradation fragment. The first specific physiological effect attributed to Ang-(1-7) was the 1988 PNAS paper by Schiavone, Khosla, Ferrario, and colleagues showing that the heptapeptide releases vasopressin from the rat hypothalamo-neurohypophysial system. Subsequent work in the late 1980s and early 1990s established that Ang-(1-7) produced vasodilation, natriuresis, and antihypertensive effects rather than simply mimicking angiotensin II at lower potency — mapping out a counter-regulatory profile distinct from the classical AT1-mediated effects. The neutral endopeptidase (neprilysin) pathway for converting angiotensin I directly to Ang-(1-7) was characterized by Yamamoto, Chappell, Brosnihan, and Ferrario in their 1992 Hypertension paper. The enzymatic and receptor architecture took shape between 2000 and 2003 in a remarkable three-year run. ACE2 was independently cloned in 2000 by two groups: Donoghue, Hsieh, Baronas, and colleagues at Millennium Pharmaceuticals (Circulation Research) and Tipnis, Hooper, Hyman, and Turner at the University of Leeds (Journal of Biological Chemistry), each describing a novel zinc carboxypeptidase homologous to ACE but functionally a monocarboxypeptidase rather than a dipeptidyl carboxypeptidase. Vickers and colleagues established in their 2002 Journal of Biological Chemistry paper that angiotensin II is the kinetically preferred ACE2 substrate, making the ACE2-mediated Ang II to Ang-(1-7) conversion the dominant route of Ang-(1-7) generation. Crackower, Sarao, Oudit, Yagil, Kozieradzki, Scanga, Oliveira-dos-Santos, da Costa, Zhang, Pei, Scholey, Ferrario, Manoukian, Chappell, Backx, Yagil, and Penninger then demonstrated in their 2002 Nature paper that ACE2-knockout mice have impaired cardiac contractility that is rescued by simultaneous ACE deletion — establishing ACE2 as essential to cardiac function in vivo and embedding it firmly in the cardioprotective half of the RAAS architecture. The receptor identification came in 2003. Robson Santos, Ana Cristina Simoes e Silva, and a multinational team including Robert Walther, Michael Bader, Maria Jose Campagnole-Santos, Robert Speth, and others published the landmark PNAS paper showing that the orphan G-protein-coupled receptor Mas (encoded by MAS1, originally identified in 1986 as a transforming gene) is the functional receptor for Ang-(1-7). Their evidence was multipronged: Ang-(1-7) bound Mas-transfected cells with high affinity, induced arachidonic acid release as a downstream readout, and Mas-knockout mice lost Ang-(1-7)-induced vasodilation in the aorta and natriuretic responses in the kidney. With ACE2, Ang-(1-7), and Mas all defined by 2003, the counter-regulatory arm of the RAAS — ACE2/Ang-(1-7)/Mas — was complete as a parallel structure to the classical ACE/Ang II/AT1 axis. Downstream signaling and physiological effects were characterized in the years that followed. Sampaio and colleagues established in 2007 (Hypertension) that Mas activates endothelial nitric oxide synthase via Akt-dependent phosphorylation. Grobe and colleagues showed in 2007 (American Journal of Physiology) that Ang-(1-7) infusion prevents Ang II-induced cardiac remodeling. Iyer and colleagues had earlier shown (2000) that prostaglandins mediate part of the antihypertensive effect of Ang-(1-7) during chronic RAAS blockade. The ACE2/Ang-(1-7)/Mas axis was systematically reviewed in the 2018 Physiological Reviews paper by Santos and colleagues, which remains the standard modern reference. The COVID-19 era brought unprecedented public visibility. Imai, Kuba, Rao, Huan, Guo, Guan, Yang, Sarao, Wada, Leong-Poi, Crackower, Fukamizu, Hui, Hein, Uhlig, Slutsky, Jiang, and Penninger had already shown in 2005 that ACE2 protects against acute lung failure (Nature) and that SARS coronavirus spike binding aggravates lung injury (Nature Medicine), providing a prepandemic foundation. When SARS-CoV-2 emerged in late 2019, Hoffmann and colleagues established in their 2020 Cell paper that SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 — directly linking the pandemic to the same ACE2 enzyme that generates Ang-(1-7). The hypothesis that SARS-CoV-2 infection reduces functional ACE2 activity and shifts RAAS balance toward unopposed angiotensin II generated extensive literature and motivated the Self and colleagues 2023 JAMA paired trials of synthetic Ang-(1-7) (TXA127) and the AT1-biased ligand TRV027 in hospitalized COVID-19 patients. Neither trial met its primary endpoint, but the mechanistic interest in the ACE2/Ang-(1-7)/Mas axis as a viral-injury-modifying pathway has persisted. Drug development around Ang-(1-7) has been pursued for decades but has not yet produced an approved product. Constant Therapeutics (formerly US Biotest) developed TXA127, an oral cyclodextrin-formulated Ang-(1-7), and tested it in Marfan syndrome aortic-root dilatation, chemotherapy-induced thrombocytopenia (a property described in early-phase work including Rodgers and colleagues), and COVID-19. Cyclic Ang-(1-7) analogues, modified-sequence variants, and small-molecule Mas agonists (notably AVE 0991, used as a research tool) have been pursued to overcome the native peptide's roughly 30-second plasma half-life. As of 2026, no Ang-(1-7) or Mas-targeted product has reached approval, though the indirect relevance of Ang-(1-7) biology to cardiovascular medicine remains substantial: ACE inhibitors and ARBs both elevate endogenous Ang-(1-7) levels, contributing to the cardioprotective and renoprotective effects of those approved drug classes beyond simple angiotensin II suppression.

How It Works

Angiotensin-(1-7) is the body's brake pedal on the same RAAS hormone system that has angiotensin II as its accelerator. Where angiotensin II tightens blood vessels, holds onto salt and water, and drives long-term vascular and cardiac scarring, Ang-(1-7) does the opposite: it relaxes blood vessels, helps the kidneys excrete sodium, and pushes back against fibrosis. Most Ang-(1-7) is made when an enzyme called ACE2 chops one amino acid off angiotensin II — converting the 'accelerator' peptide into the 'brake' peptide. It then docks onto a receptor called Mas to deliver its calming signals. The same ACE2 enzyme is the one SARS-CoV-2 hijacks to enter cells, which is why this previously obscure peptide became a topic of mainstream COVID-19 research starting in 2020. Standard blood pressure pills like lisinopril and losartan don't act on Ang-(1-7) directly, but they raise endogenous Ang-(1-7) levels as a side effect, and that's now thought to be part of why those drugs work as well as they do for the heart and kidneys.

Angiotensin-(1-7) is a 7-amino-acid peptide (Asp-Arg-Val-Tyr-Ile-His-Pro) generated through two principal enzymatic routes within the renin-angiotensin-aldosterone system. The dominant pathway is ACE2-mediated cleavage of angiotensin II: ACE2 (angiotensin-converting enzyme 2), a zinc monocarboxypeptidase cloned independently in 2000 by Donoghue and colleagues at Millennium Pharmaceuticals (Circulation Research) and Tipnis, Hooper, Hyman, and Turner at the University of Leeds (Journal of Biological Chemistry), removes the C-terminal phenylalanine from the 8-residue angiotensin II to release the 7-residue Ang-(1-7). Vickers and colleagues established in 2002 (Journal of Biological Chemistry) that angiotensin II is the strongly preferred substrate of ACE2 over angiotensin I, with kinetics roughly 400-fold higher for the octapeptide. A secondary pathway converts angiotensin I directly to Ang-(1-7) through neutral endopeptidase (neprilysin, NEP), prolyl endopeptidase, and thimet oligopeptidase — Yamamoto, Chappell, Brosnihan, and Ferrario characterized neprilysin's role in this conversion in their 1992 Hypertension paper. The neprilysin pathway becomes more prominent during ACE inhibition, when angiotensin I substrate accumulates, and is part of why ACE inhibitors and ARBs both elevate circulating Ang-(1-7) — a mechanistic feature relevant to the cardioprotective benefit of those drug classes. Ang-(1-7) signals through the Mas receptor, a G-protein-coupled receptor encoded by MAS1, originally identified in 1986 as a transforming gene in NIH3T3 cells and long classified as an orphan GPCR. Santos, Simoes e Silva, Maric, Sliwa, Machado, de Buhr, Heringer-Walther, Pinheiro, Lopes, Bader, Mendes, Lemos, Campagnole-Santos, Schultheiss, Speth, and Walther established Mas as the functional Ang-(1-7) receptor in their landmark 2003 PNAS paper: Ang-(1-7) bound Mas-transfected cells with high affinity, induced arachidonic acid release, and Mas-knockout mice lost Ang-(1-7)-induced vasodilation in the aorta and natriuretic responses in the kidney. Downstream Mas signaling involves Gi/o coupling and direct activation of endothelial nitric oxide synthase via Akt-dependent pathways — Sampaio and colleagues showed in 2007 (Hypertension) that Ang-(1-7) at Mas activates Akt-eNOS-NO-cGMP signaling, providing the cellular basis for the vasodilatory phenotype. Additional downstream effects include reduced reactive oxygen species generation (opposing AT1-driven NADPH oxidase activation), inhibition of MAP kinase cascades that drive hypertrophy and proliferation, and prostaglandin-mediated antihypertensive effects (Iyer and colleagues 2000). Functionally, the ACE2/Ang-(1-7)/Mas axis opposes the classical ACE/Ang II/AT1 axis at essentially every level. In the vasculature, Ang-(1-7) produces endothelium-dependent vasodilation that opposes Ang II-mediated vasoconstriction. In the kidney, Ang-(1-7) promotes natriuresis and opposes Ang II-driven sodium retention; Mas-receptor signaling reduces tubular sodium reabsorption and protects against proteinuria in models of diabetic and non-diabetic kidney disease. In the heart, Ang-(1-7) is anti-fibrotic and antiproliferative, opposing Ang II-driven myocardial hypertrophy and interstitial fibrosis — Grobe and colleagues showed in 2007 (American Journal of Physiology) that Ang-(1-7) infusion prevents Ang II-induced cardiac remodeling. The Crackower and Penninger 2002 Nature paper established that ACE2 is essential for normal cardiac contractility, with ACE2-knockout mice showing reduced contractile function that is rescued by simultaneous deletion of ACE — placing ACE2 firmly in the cardioprotective half of the RAAS. Ang-(1-7) has additional documented actions including baroreflex modulation, central effects on cardiovascular regulation in brainstem nuclei, anti-inflammatory effects in vascular and pulmonary tissue, and pro-resolution signaling in models of acute lung injury. Schiavone and colleagues showed in 1988 (PNAS) that Ang-(1-7) releases vasopressin from the rat hypothalamo-neurohypophysial system — one of the earliest specific physiological effects attributed to the peptide, and a contrast to its predominantly counter-regulatory profile elsewhere. The COVID-19 literature added a substantial chapter. Hoffmann and colleagues established in 2020 (Cell) that SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 — the spike protein binds ACE2 with high affinity and is primed for membrane fusion by TMPRSS2-mediated cleavage. The Imai and colleagues 2005 Nature and Nature Medicine papers had previously shown that ACE2 protects against acute lung injury and that SARS coronavirus spike binding aggravates lung injury, providing the prepandemic foundation. Several lines of evidence suggest that SARS-CoV-2 infection reduces functional cell-surface ACE2 activity, which would mechanistically shift RAAS balance toward unopposed angiotensin II at AT1 and reduce Ang-(1-7) generation — providing the rationale for trials of synthetic Ang-(1-7) and AT1-biased ligands in hospitalized COVID-19 (Self and colleagues, JAMA 2023). Those trials did not meet their primary endpoints, but the mechanistic framework around the ACE2/Ang-(1-7)/Mas axis as a viral-injury-modifying pathway has persisted. Pharmacokinetically, the peptide is rapidly cleared. Native Ang-(1-7) has a plasma half-life of approximately 30 seconds, with degradation by ACE (which cleaves Ang-(1-7) to Ang-(1-5)) and other peptidases. This very short half-life is why intermittent administration is pharmacologically irrational and why drug development efforts have focused on oral cyclodextrin formulations (TXA127), cyclic Ang-(1-7) analogues, and small-molecule Mas agonists.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Angiotensin-(1-7):

• 01Whether direct Ang-(1-7) supplementation, Mas-receptor agonism, or biased Mas signaling will ultimately produce a therapeutic-grade approved drug for any cardiovascular, renal, or pulmonary indication — the mechanistic case is strong, but two decades of investigational development have not yet converged on regulatory success.
• 02Whether the failure of synthetic Ang-(1-7) (TXA127) and the AT1-biased ligand TRV027 to meet primary endpoints in the Self and colleagues 2023 JAMA COVID-19 trials reflects a real absence of clinical benefit, suboptimal patient selection, suboptimal dosing, or a pharmacokinetic limitation of the current preparations — and whether revised trial design with a different population, biomarker, or dose could yet establish efficacy.
• 03The clinical relevance of measured Ang-(1-7) levels as a biomarker of RAAS balance — whether plasma or tissue Ang-(1-7) measurement can guide dosing of ACE inhibitors, ARBs, or sacubitril/valsartan in individual patients, and whether genetic or environmental variation in ACE2 activity meaningfully predicts cardiovascular phenotype.
• 04Whether the Ang-(1-9) / AT2 receptor pathway (a parallel ACE2-derived counter-regulatory branch) provides therapeutic targets distinct from Ang-(1-7) / Mas, and whether dual-pathway agents would offer additional benefit.
• 05Whether SARS-CoV-2-induced ACE2 dysregulation has detectable durable effects on RAAS balance and Ang-(1-7) signaling in post-COVID patients, and whether long-COVID phenotypes (cardiovascular, renal, pulmonary, neurological) reflect persisting ACE2/Ang-(1-7)/Mas perturbation that could be therapeutically targeted.
• 06The contribution of brain Ang-(1-7) and Mas signaling to baroreflex modulation, autonomic balance, and cardiovascular regulation in humans — extensive rodent literature exists, but human translation is essentially absent.
• 07Whether Ang-(1-7) and Mas signaling have therapeutic relevance in pulmonary fibrosis, diabetic kidney disease, or other fibrotic conditions where the anti-fibrotic preclinical signature is robust but clinical translation has not been pursued at scale.
• 08The pharmacokinetic and pharmacodynamic optimization of cyclic and modified Ang-(1-7) analogues — whether sufficiently durable agonism can be achieved without losing receptor selectivity or introducing off-target effects.

Forms & Administration

Ang-(1-7) has no FDA-approved formulation in any jurisdiction. Native synthetic Ang-(1-7) is used in research as an IV infusion (the very short plasma half-life precludes intermittent dosing), in subcutaneous administration in animal models, and in receptor-binding and signaling assays. Investigational therapeutic preparations include TXA127, an oral hydroxypropyl-beta-cyclodextrin-formulated Ang-(1-7) developed by Constant Therapeutics (formerly US Biotest) and tested in Marfan syndrome, chemotherapy-induced thrombocytopenia, and COVID-19; cyclic Ang-(1-7) analogues (e.g., cyclized through thioether bonds) designed to resist proteolytic degradation; and small-molecule Mas agonists such as AVE 0991, which has been used as a Mas-active research tool in animal studies. Compounded Ang-(1-7) sold through peptide marketplaces has no validated clinical use, no quality-controlled reference product, and no established dosing regimen.

Common Questions

Who Angiotensin-(1-7) Is NOT For

Drug & Supplement Interactions

Because no Ang-(1-7) product is approved, the validated human drug-interaction profile is limited. The most clinically meaningful interaction is the cumulative effect with other RAAS-modifying drugs. ACE inhibitors (lisinopril, enalapril, ramipril, and class-mates) elevate endogenous Ang-(1-7) levels by two mechanisms: they reduce ACE-mediated degradation of Ang-(1-7) (ACE cleaves Ang-(1-7) to Ang-(1-5), so ACE inhibition slows Ang-(1-7) clearance) and they redirect angiotensin I metabolism toward neprilysin-mediated Ang-(1-7) generation. Adding exogenous Ang-(1-7) to an ACE inhibitor would compound this elevation. Angiotensin receptor blockers (ARBs — losartan, valsartan, and class-mates) similarly elevate endogenous Ang-(1-7) by raising upstream substrate availability and redirecting metabolism. Direct renin inhibitors (aliskiren) reduce upstream substrate and would attenuate endogenous Ang-(1-7) generation, although this has not been a prominent clinical concern. Neprilysin inhibitors are an important interaction category. Sacubitril (paired with valsartan as ARNI for heart failure with reduced ejection fraction) inhibits the same neprilysin that generates Ang-(1-7) from angiotensin I. The net effect on Ang-(1-7) levels in patients on sacubitril/valsartan is competing — reduced neprilysin-mediated generation balanced against elevated upstream substrate from ARB action — and the pharmacology is not fully resolved in human studies. Patients on sacubitril/valsartan who receive exogenous Ang-(1-7) would not have the augmentation effect seen with classical ACE inhibitor therapy. Mineralocorticoid receptor antagonists (spironolactone, eplerenone, finerenone) act downstream of angiotensin II at the aldosterone level and do not directly modify Ang-(1-7) generation, but their use in combination with multiple RAAS-modifying agents raises hyperkalemic risk that would be a concern in any cumulative regimen. Vasoactive agents in critical care (vasopressors, vasodilators) would have additive or counteracting hemodynamic effects with exogenous Ang-(1-7), although clinical experience is essentially absent. Anticoagulants and antiplatelet agents may interact with the documented thrombogenic pharmacodynamic property of Ang-(1-7) characterized in the oncology development program — worth flagging mechanistically even though clinical thromboembolic events have not been a prominent signal. Because Ang-(1-7) is cleared by peptidase activity (ACE, dipeptidyl peptidase-4, and others) rather than cytochrome P450 metabolism, classical CYP-mediated drug interactions are not anticipated.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions