Angiotensin-(1-7) for Cardiovascular Health in Aging

Overseen By Amy Arnold, PhD

Age: 65+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Milton S. Hershey Medical Center

Must not be taking: Anticoagulants, Glucocorticoids, Stimulants, others

Disqualifiers: Diabetes, Hypertension, Cardiovascular disease, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 visits, each lasting approximately 4 hours

26 Participants Needed

Trial Summary

What is the purpose of this trial?

Aging is an independent risk factor for developing hypertension and cardiovascular disease; however, the mechanisms underlying age-related cardiovascular disease remain poorly understood. One hallmark of aging is an increase in sympathetic nervous system activity, which can decrease the number and/or sensitivity of β2 adrenergic receptors to reduce dilation of blood vessels and increase blood pressure. Identifying new targets to restore vascular β2 adrenergic receptor signaling may help reduce cardiovascular risk in aging. This study will test the hypothesis that angiotensin-(1-7), a protective hormone of the renin-angiotensin system, can reduce cardiovascular sympathetic outflow and blood pressure and improve endothelial function in older healthy humans.

Will I have to stop taking my current medications?

The trial requires that you do not take medications that influence sympathetic activity, anticoagulants, chronic systemic glucocorticoids, or investigational drugs within a month before the study. If you are on these medications, you may need to stop them to participate.

What evidence supports the effectiveness of the drug Angiotensin-(1-7) for cardiovascular health in aging?

Research suggests that Angiotensin-(1-7) may help protect the heart and blood vessels by lowering blood pressure, reducing tissue damage, and preventing harmful changes in the heart and arteries. It has shown potential benefits in animal studies for conditions like high blood pressure and heart disease, although more human studies are needed to confirm these effects. ^{1 2 3 4 5}

Is Angiotensin-(1-7) safe for human use?

Angiotensin-(1-7) has shown protective effects in cardiovascular health, such as reducing blood pressure and protecting heart cells, in various studies. While it has potential benefits, more research is needed to fully understand its safety and effectiveness in humans. ^{1 2 5 6 7}

How is the drug Angiotensin-(1-7) unique for cardiovascular health in aging?

Angiotensin-(1-7) is unique because it targets the protective branch of the renin-angiotensin system, offering anti-aging benefits like reducing blood pressure, improving insulin sensitivity, and protecting against vascular aging. Unlike other treatments, it has anti-inflammatory and antioxidant effects, and it promotes repair and protection of blood vessels, making it a promising option for preventing cardiovascular aging. ^{1 2 6 8 9}

Research Team

Amy Arnold, PhD

Principal Investigator

Pennsylvania State University College of Medicine

Eligibility Criteria

This trial is for healthy older adults aged 65-80 with normal blood pressure and BMI between 18.5 and 30 kg/m2. Participants must be fluent in English, able to consent, not on certain medications or have conditions like impaired liver/renal function, anemia, diabetes, serious cardiovascular or cerebrovascular disease.

Inclusion Criteria

Fluent in written and spoken English

I am between 65 and 80 years old.

My gender or ethnicity does not limit my participation.

Exclusion Criteria

Prisoners

I have difficulty making decisions due to a mental condition.

Highly trained athletes

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin-(1-7) or saline infusion to assess cardiovascular effects

2 visits, each lasting approximately 4 hours

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

Treatment Details

Interventions

• Angiotensin-(1-7)
• Saline

Trial Overview The study investigates if angiotensin-(1-7), a hormone that could help the heart and blood vessels work better, can lower sympathetic nervous system activity and improve blood vessel function in aging individuals compared to saline (a placebo).

Participant Groups

Group I: Angiotensin-(1-7) Experimental Treatment 1 Intervention

Participants will receive intravenous angiotensin-(1-7) at one study visit for 110 minutes. Angiotensin-(1-7) will be given in escalating doses of 2 ng/kg/min, 4 ng/kg/min, and 8 ng/kg/min. Each of these doses will be infused for 10 minutes. Following the dose escalation, angiotensin-(1-7) will be given at 8 ng/kg/min for an additional 80 minutes. Infusion rates will be calculated for each participant based on body mass.

Group II: Saline Placebo Group 1 Intervention

Participants will receive intravenous saline at one study visit for 110 minutes total. The volume of saline will match the volume of angiotensin-(1-7) infused. Infusion rates will be calculated for each participant based on body mass.

Angiotensin-(1-7) is already approved in United States, European Union for the following indications:

Approved in United States as TXA127 for:

• Duchenne muscular dystrophy (DMD)
• Limb-girdle muscular dystrophy (LGMD)
• Congenital muscular dystrophy MDC1A
• Marfan syndrome
• Dystrophic Epidermolysis Bullosa (DEB)
• Pulmonary arterial hypertension
• Myelodysplastic Syndrome (MDS)

Approved in European Union as TXA127 for:

• Duchenne muscular dystrophy (DMD)

Who Is Running the Clinical Trial?

Milton S. Hershey Medical Center

Lead Sponsor

Trials

515

Recruited

2,873,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Angiotensin-(1-7) has shown promising effects in cardiovascular health, including antihypertensive, antihypertrophic, antifibrotic, and antithrombotic properties, based on various animal studies.

Despite its potential benefits, the clinical use of angiotensin-(1-7) is limited due to its unfavorable pharmacokinetic properties, necessitating the development of more stable analogues or specific delivery methods to enhance its therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives. Iusuf, D., Henning, RH., van Gilst, WH., et al.[2016]

Angiotensin(Ang)-(1-7) has protective effects against vascular aging, including reducing cell senescence, inflammation, and oxidative stress, which are key factors in the development of vascular diseases.

This heptapeptide also improves endothelial function, reduces fibrosis and calcification, and promotes blood vessel repair, making it a promising candidate for preventing vascular aging and associated frailty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7), a protective peptide against vascular aging. Valencia, ., Shamoon, L., Romero, A., et al.[2022]

Angiotensin (Ang)-(1-7) has been linked to blood pressure regulation, primarily through indirect mechanisms involving bradykinin and nitric oxide signaling, based on various studies in humans and animal models.

In addition to its role in blood pressure, Ang-(1-7) exhibits direct cardioprotective effects, such as reducing heart muscle hypertrophy and fibrosis, suggesting its potential as a therapeutic target for cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) as an antihypertensive, antifibrotic target. Katovich, MJ., Grobe, JL., Raizada, MK.[2021]

Angiotensin-(1-7) is a promising hormone that counteracts the harmful effects of angiotensin II, showing potential benefits such as lowering blood pressure and reducing cardiovascular risks through its action on specific receptors in key organs like the heart and kidneys.

While animal studies suggest that angiotensin-(1-7) has various protective cardiovascular effects, there is a lack of clinical research in humans, which hinders the development of effective treatments based on this hormone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): Translational Avenues in Cardiovascular Control. Medina, D., Arnold, AC.[2020]

Angiotensin-(1-7) (Ang-[1-7]) protects heart cells from high glucose-induced damage by inhibiting the reactive oxygen species-leptin-p38 MAPK/ERK1/2 pathways, which are activated during diabetic conditions.

In laboratory tests on H9c2 heart cells, Ang-(1-7) treatment led to increased cell viability, reduced apoptosis, and lower reactive oxygen species production, demonstrating its potential as a therapeutic agent in diabetic cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Lei, Y., Xu, Q., Zeng, B., et al.[2022]

In both adult and aged normotensive rats, Angiotensin (1-7) effectively reduced blood pressure, indicating its vasodilatory properties are preserved with aging, although the mechanisms involved change.

While Ang (1-7) primarily acted through angiotensin type 2 receptors (AT(2)R) in younger rats, in aged rats, both AT(2)R and Mas receptors (MasR) contributed to its blood pressure-lowering effects, suggesting a shift in receptor involvement with age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. Bosnyak, S., Widdop, RE., Denton, KM., et al.[2021]

Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide that has shown beneficial effects against various cardiovascular issues, including heart failure, hypertension, and cardiac arrhythmia.

Research indicates that Ang-(1-7) may also have therapeutic potential beyond cardiovascular diseases, potentially impacting conditions like renal disease, preeclampsia, and cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacology and new perspectives in cardiovascular treatments. Trask, AJ., Ferrario, CM.[2018]

Chronic treatment with Angiotensin (Ang)-(1-7) significantly lowered blood pressure in aged mice, indicating its potential as a therapeutic option for managing age-related hypertension.

Ang-(1-7) improved insulin sensitivity in aged mice to levels comparable to young mice, suggesting it may help mitigate metabolic issues associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. Miller, AJ., Bingaman, SS., Mehay, D., et al.[2021]

A transgenic rat model overexpressing human ACE2 showed protection against age-related kidney decline, with significantly less albuminuria compared to standard rats, indicating a potential therapeutic role for the ACE2/Ang(1-7)/MAS axis.

The study found that while young transgenic rats had normal kidney function, aged standard rats experienced severe kidney damage, suggesting that enhancing ACE2 activity could mitigate kidney disease associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgenic angiotensin-converting enzyme 2 overexpression in the rat vasculature protects kidneys from ageing-induced injury. Sanad, AM., Qadri, F., Popova, E., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives. [2016]

2. United States pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7), a protective peptide against vascular aging. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) as an antihypertensive, antifibrotic target. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): Translational Avenues in Cardiovascular Control. [2020]

5. Japan pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacology and new perspectives in cardiovascular treatments. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Transgenic angiotensin-converting enzyme 2 overexpression in the rat vasculature protects kidneys from ageing-induced injury. [2023]