Angiotensin-(1-7)

1. Overview

Angiotensin-(1-7), abbreviated Ang-(1-7), is an endogenous heptapeptide with the amino acid sequence Asp-Arg-Val-Tyr-Ile-His-Pro (DRVYIHP) and a molecular weight of 899.02 g/mol [1][6]. It is a biologically active component of the renin-angiotensin system (RAS) that was first identified as having biological activity in the late 1980s when Santos and colleagues demonstrated it was a major product of angiotensin I metabolism in brain tissue, and Schiavone et al. reported its first biological effect [6]. The peptide is also known by its pharmaceutical development name TXA127 (generic name: talfirastide) when formulated as a drug candidate by Constant Therapeutics (formerly Tarix Pharmaceuticals).

Ang-(1-7) is primarily produced by the enzymatic action of angiotensin-converting enzyme 2 (ACE2) on angiotensin II, and to a lesser extent by other endopeptidases acting on angiotensin I [2][6]. Its identification as the endogenous ligand for the G protein-coupled receptor Mas in 2003 by Santos et al. was a landmark discovery that established the ACE2/Ang-(1-7)/Mas axis as a counter-regulatory arm of the RAS, opposing the vasoconstrictive, pro-inflammatory, and pro-fibrotic actions of the classical ACE/angiotensin II/AT1 receptor axis [1][7]. This discovery fundamentally reshaped the understanding of the RAS from a linear vasoconstrictor pathway to a dual-axis system with both pathological and protective arms.

Ang-(1-7) gained renewed attention during the COVID-19 pandemic because SARS-CoV-2 enters cells via ACE2, the same enzyme responsible for generating Ang-(1-7) from angiotensin II. Viral-mediated downregulation of ACE2 is hypothesized to shift the RAS balance toward angiotensin II predominance, reducing protective Ang-(1-7) levels and contributing to the inflammatory organ damage seen in severe COVID-19 [8][15].

Molecular Weight

899.02 g/mol

Molecular Formula

C41H62N12O11

Sequence

Asp-Arg-Val-Tyr-Ile-His-Pro (DRVYIHP)

Half-life

~10 seconds (plasma); 20-30 minutes (subcutaneous)

Primary Receptor

Mas receptor (MasR), a G protein-coupled receptor

Producing Enzyme

ACE2 (angiotensin-converting enzyme 2)

Routes Studied

Subcutaneous injection, intravenous infusion, oral (HPbetaCD complex)

FDA Status

Not approved; TXA127 in phase 2 clinical trials (Constant Therapeutics)

2. Mechanism of Action

Ang-(1-7) exerts its biological effects primarily through binding to the Mas receptor (MasR), a G protein-coupled receptor expressed in the heart, blood vessels, kidneys, brain, lungs, liver, and other tissues [1][6]. Upon binding, Mas activates intracellular signaling cascades that are largely opposite to those triggered by angiotensin II at the AT1 receptor.

Vasodilation and blood pressure regulation: Ang-(1-7) promotes vasodilation through stimulation of endothelial nitric oxide synthase (eNOS) and subsequent nitric oxide (NO) production. It also potentiates the vasodilatory effects of bradykinin, contributing to blood pressure reduction [6]. In the central nervous system, Ang-(1-7) acts at the nucleus tractus solitarii and ventrolateral medulla to modulate baroreflex sensitivity and sympathetic outflow.

Anti-inflammatory signaling: The peptide suppresses NF-kappaB signaling and reduces production of pro-inflammatory cytokines including IL-6, TNF-alpha, and IL-1beta [7][9][10]. In macrophages, Ang-(1-7) decreases LPS-induced inflammatory responses through Mas-dependent mechanisms [9]. This anti-inflammatory activity has been demonstrated across cardiovascular, renal, pulmonary, and neurological tissue contexts.

Anti-fibrotic effects: Ang-(1-7) inhibits epithelial-to-mesenchymal transition (EMT) and fibrosis by suppressing ERK1/2 phosphorylation and TGF-beta1/Smad signaling pathways [7]. These effects are relevant to cardiac, renal, pulmonary, and hepatic fibrosis models.

Anti-proliferative and anti-angiogenic actions: In cancer contexts, Ang-(1-7) inhibits cell proliferation, reduces tumor-associated angiogenesis via repression of HIF-1alpha and placental growth factor (PlGF), and attenuates cancer-associated fibroblast activity [4][5][12].

Novel AT1 receptor mechanism: A 2017 discovery revealed that Ang-(1-7) can also act as an endogenous beta-arrestin-biased agonist at the AT1 receptor itself, activating cardioprotective beta-arrestin signaling without triggering the deleterious Gq-mediated pathways that angiotensin II activates at the same receptor. This provides an additional mechanism for its cardioprotective effects independent of Mas [6].

The selective Mas receptor antagonist A779 (D-Ala7-Ang-(1-7)) blocks Ang-(1-7) effects in experimental models, confirming the Mas-dependent nature of most observed biological activities.

3. Researched Applications

Cardiovascular Protection

Evidence level: Moderate (extensive animal data; limited human data)

Ang-(1-7) has demonstrated broad cardioprotective effects in preclinical models. In rats with myocardial infarction, chronic Ang-(1-7) infusion preserved cardiac function and attenuated heart failure development [3]. The peptide exhibits antihypertensive, antihypertrophic, antiarrhythmic, and antithrombotic properties [6]. It reduces cardiac fibrosis, improves endothelial function, and has been shown to activate the sodium pump and hyperpolarize cardiomyocyte membranes, increasing conduction velocity and reducing arrhythmia vulnerability. In diabetic db/db mice, short-term Ang-(1-7) administration improved cardiac function and restored circulating progenitor cell numbers [6]. A systematic review found preclinical evidence supporting a cardioprotective role in heart failure models, though only one small intervention study in 8 human heart failure patients has been published.

Renal Protection

Evidence level: Moderate (animal studies)

The ACE2/Ang-(1-7)/Mas axis exerts nephroprotective effects across multiple kidney disease models. In stroke-prone spontaneously hypertensive rats, chronic Ang-(1-7) reduced proteinuria and ameliorated glomerular and tubular damage independent of blood pressure effects, with decreased renal inflammation markers [6]. The peptide attenuates obstructive nephropathy by suppressing TGF-beta1/Smad-mediated fibrosis and apoptosis. In sepsis-induced acute kidney injury, Ang-(1-7) protects by inhibiting NF-kappaB signaling. Evidence supports a protective role in hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and pre-eclampsia models [6][7].

Cancer and Anti-Angiogenesis

Evidence level: Preliminary (Phase I/II clinical trials)

Ang-(1-7) has been evaluated as an anti-cancer agent based on its antiproliferative and anti-angiogenic properties. A Phase I trial in 18 patients with advanced solid tumors established the subcutaneous dose of 400 mcg/kg/day as the recommended Phase II dose, with antiangiogenic activity linked to PlGF suppression [4]. A subsequent Phase II trial in metastatic sarcoma patients treated with 20 mg/day SC showed the drug was well-tolerated, with median progression-free survival of 2.7 months and median overall survival of 10.2 months [5]. Preclinical studies have demonstrated efficacy against lung, breast, prostate, nasopharyngeal, and liver tumor growth through regulation of proliferation, angiogenesis, and tumor-associated inflammation [12].

COVID-19 and Respiratory Disease

Evidence level: Preliminary (Phase II pilot trial)

SARS-CoV-2 binds to ACE2 for cell entry, potentially downregulating this enzyme and reducing Ang-(1-7) production while allowing angiotensin II to accumulate. Patients with severe COVID-19 show reduced circulating Ang-(1-7) levels and elevated Ang II/Ang-(1-7) ratios, with ratios above 3.45 associated with higher mortality [15]. A randomized, placebo-controlled pilot study of TXA-127 (10 mcg/kg/day IV) in severe COVID-19 patients demonstrated safety and tolerability but showed no significant difference in intubation rates, length of stay, or mortality versus placebo [8]. The peptide has also been shown to attenuate SARS-CoV-2 spike protein-induced IL-6 and IL-8 production in alveolar epithelial cells through Mas receptor activation.

Neuroprotection and Stroke Recovery

Evidence level: Preliminary (preclinical; Phase II trial ongoing)

Preclinical studies have demonstrated anti-inflammatory and neuroprotective effects of Ang-(1-7) in rodent models of cognitive impairment, Alzheimer's disease, Parkinson's disease, stroke, and traumatic brain injury. Constant Therapeutics dosed the first patient in January 2024 in a Phase 2 randomized, placebo-controlled, double-blind trial of TXA127 for ischemic stroke recovery, enrolling patients 6-24 months post-stroke to evaluate motor and sensory function improvement over 3 months of treatment. This trial is being conducted at Sheba Medical Center in Israel and aims to enroll 50 patients. Supporting this clinical direction, a February 2025 preclinical study in a rodent white matter stroke model (rNAION) demonstrated that Ang-(1-7) provides potent long-term neurorepair and neuroregeneration, representing the first compound shown to be functionally effective when administered at least 1 day after ischemic induction.

Muscular Dystrophy

Evidence level: Preliminary (Phase II trial ongoing)

TXA127 has shown anti-fibrotic effects in animal models of Duchenne muscular dystrophy (DMD) and epidermolysis bullosa. Constant Therapeutics dosed the first patient in March 2024 in a Phase 2 open-label, multi-center trial for DMD-associated cardiomyopathy, evaluating safety and efficacy in non-ambulatory patients aged 16 and older receiving systemic glucocorticoids, with 6 months of treatment and an optional 12-month extension. The trial is being conducted in Israel at Sheba Medical Center and Hadassah Medical Center. As of early 2026, both the stroke and DMD trials are ongoing with results anticipated.

Hematopoietic Recovery

Evidence level: Preliminary (clinical trial)

TXA127 has been studied for its ability to accelerate neutrophil engraftment and platelet recovery following hematopoietic stem cell transplantation. A clinical trial (NCT01882374) evaluated TXA127 for reducing acute graft-versus-host disease in patients undergoing double umbilical cord blood transplantation, based on the observation that Ang-(1-7) appears to promote rapid production of neutrophils and platelets.

4. Clinical Evidence Summary

5. Dosing in Research

The following table summarizes doses used in published research studies. These are not therapeutic recommendations. Angiotensin-(1-7) is not approved for human use outside of clinical trials, and optimal therapeutic dosing has not been established.

6. Safety and Side Effects

In preclinical toxicology studies, subcutaneous administration of Ang-(1-7) at doses up to 10 mg/kg/day for 28 days produced no detectable toxicities in rats or canines [6]. The peptide has a rapid plasma clearance primarily mediated by ACE, with a very short circulating half-life of approximately 10 seconds for the free peptide, though subcutaneous administration extends the effective half-life to 20-30 minutes.

In the Phase I cancer trial, dose-limiting toxicities at 700 mcg/kg included one grade 4 stroke and one grade 3 reversible cranial neuropathy. At the recommended Phase II dose of 400 mcg/kg, the drug was generally well-tolerated [4]. In the Phase II sarcoma trial at 20 mg/day, no dose de-escalation was required [5]. In the COVID-19 pilot trial, IV infusion at 10 mcg/kg/day was safe, with adverse effects limited to cough, headache, and chest discomfort; notably, hypotension was not observed despite the vasodilatory mechanism [8].

Key safety considerations and unknowns:

• Hypotension risk: Although Ang-(1-7) is a vasodilator, clinically significant hypotension has not been a prominent finding in trials to date. However, careful blood pressure monitoring is warranted, especially in combination with antihypertensive medications.
• Thrombotic events: The grade 4 stroke observed in the Phase I trial at the highest dose level raises concern about potential prothrombotic or vascular events at supratherapeutic doses, though Ang-(1-7) is generally considered antithrombotic.
• Short half-life challenges: The extremely short plasma half-life necessitates either continuous infusion, frequent subcutaneous injections, or novel delivery systems (such as the oral HPbetaCD complex) for sustained therapeutic effect.
• Cancer context: While Ang-(1-7) demonstrates anti-tumor properties, its effects on angiogenesis are context-dependent, and long-term effects on tumor biology in humans require further evaluation.
• Drug interactions: Interactions with ACE inhibitors, ARBs, and other RAS-modulating drugs have not been systematically evaluated in humans, though preclinical evidence suggests potential synergistic or additive effects.
• Pregnancy: Given the critical role of the RAS in fetal development, Ang-(1-7) use during pregnancy has not been evaluated and should be considered contraindicated until safety data become available.

7. Drug Delivery and Formulation

A significant challenge for Ang-(1-7) as a therapeutic agent is its extremely short plasma half-life. Several approaches have been developed to address this limitation:

Subcutaneous injection extends the effective duration compared to IV bolus, with time to maximum plasma concentration of 15 minutes in rats and 26 minutes in canines. This is the route used in most clinical trials to date [4][5].

Continuous IV infusion was used in the COVID-19 trial (TXA-127) to maintain steady-state plasma levels [8].

Oral HPbetaCD complex: Researchers led by Santos and colleagues developed an oral formulation using hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion complexes that protect the peptide from gastric degradation. Oral HPbetaCD/Ang-(1-7) increased plasma levels 12-fold at 6 hours post-administration in rats and demonstrated cardioprotective effects in myocardial infarction models over 60 days of daily oral dosing [13]. This formulation has shown efficacy in preclinical models of thrombosis, metabolic syndrome, erectile dysfunction, type 2 diabetes, hypertension, and muscular dystrophy.

Emerging approaches include PNA5, a novel Ang-(1-7) receptor agonist with improved pharmacokinetic properties, and DIZE (diminazene aceturate), an ACE2 activator that indirectly increases endogenous Ang-(1-7) production [14].

8. Related Peptides

See also: BPC-157 (Body Protection Compound-157), Semaglutide, Tirzepatide

9. References

1. [1] Santos RAS, Simoes e Silva AC, Maric C, Silva DMR, Machado RP, de Buhr I, et al. (2003). Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences. DOI PubMed
2. [2] Santos RAS, Ferreira AJ, Verano-Braga T, Bader M. (2013). Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. Journal of Endocrinology. DOI PubMed
3. [3] Ferreira AJ, Santos RAS, Almeida AP. (2002). Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation. DOI PubMed
4. [4] Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM. (2009). Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone. Clinical Cancer Research. DOI PubMed
5. [5] Savage PD, Lovato J, Engelbrecht H, Torti FM, Atkins JN, Talamonti MS, et al. (2016). Phase II trial of angiotensin-(1-7) for the treatment of patients with metastatic sarcoma. Sarcoma. DOI PubMed
6. [6] Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. (2018). The ACE2/angiotensin-(1-7)/Mas axis of the renin-angiotensin system: focus on angiotensin-(1-7). Physiological Reviews. DOI PubMed
7. [7] Simoes e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. (2013). ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. British Journal of Pharmacology. DOI PubMed
8. [8] Wagener G, Gullberg AT, Lee J, Yang J, Wang HM, Maruthur NM, et al. (2022). A randomized, placebo-controlled, double-blinded pilot study of angiotensin 1-7 (TXA-127) for the treatment of severe COVID-19. Critical Care. DOI PubMed
9. [9] Souza LL, Costa-Neto CM. (2012). Angiotensin-(1-7) decreases LPS-induced inflammatory response in macrophages. Journal of Cellular Physiology. DOI PubMed
10. [10] Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes-e-Silva AC. (2017). The anti-inflammatory potential of ACE2/angiotensin-(1-7)/Mas receptor axis: evidence from basic and clinical research. Current Drug Targets. DOI PubMed
11. [11] Passos-Silva DG, Verano-Braga T, Santos RAS. (2013). Angiotensin-(1-7): beyond the cardio-renal actions. Clinical Science. DOI PubMed
12. [12] Peiris-Pages M, Mayfield B, Engelbrecht H, Gallagher PE, Tallant EA. (2012). Reverse translation of phase I biomarker findings links the activity of angiotensin-(1-7) to repression of hypoxia inducible factor-1alpha in vascular sarcomas. BMC Cancer. DOI PubMed
13. [13] Marques FD, Ferreira AJ, Sinisterra RD, Jacoby BA, Sousa FB, Caliari MV, et al. (2011). An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension. DOI PubMed
14. [14] Qaradakhi T, Gadanec LK, McSweeney KR, Tacey A, Apostolopoulos V, Levinger I, et al. (2020). The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clinical and Experimental Pharmacology and Physiology. DOI PubMed
15. [15] Seyedmehdi SM, Nabavi N, Yadegari A, Keshtkar M, Shafiei M. (2022). Patients with severe COVID-19 have reduced circulating levels of angiotensin-(1-7): a cohort study. Health Science Reports. DOI PubMed