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Updated: May 30, 2026
Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model
Published on: February 10, 2023
Systemic delivery of BH4 anti-apoptotic peptide using CPPs prevents cardiac ischemia-reperfusion injuries in vivo
Prisca Boisguerin1, Christelle Redt-Clouet, Alicia Franck-Miclo
1UMR 5235 CNRS, Universités Montpellier 1 et 2, Place Eugene Bataillon, 34095 Montpellier, France. prisca.boisguerin@univ-montp2.fr
Abstract:
There is an obvious need to develop pharmacological strategies to protect the heart in patients suffering from acute myocardial infarction. Apoptosis was evidenced as a main contributor of myocardial ischemia-reperfusion (IR) injury. Our cardioprotective strategy was based on the use of four cell penetrating peptides (CPP: Tat, (RXR)4, Bpep and Pip2b) which were conjugated to the BH4-peptide, derived from the BH4 domain of the Bcl-xL anti-apoptotic protein. These CPP-BH4 conjugates were able to reduce staurosporine-induced apoptosis in primary cardiomyocytes in vitro. Although Pip2b-BH4 was more efficient in terms of cellular uptake, it was as efficient as Tat-BH4 for its anti-apoptotic activity. As required for potential therapeutic application their cardioprotective effects were evaluated in an in vivo mouse model of myocardial IR injury. Our results clearly show that a single low dose (1 mg/kg) injection of Tat-BH4 and Pip2b-BH4 administered intravenously 5 min before reperfusion was able to drastically reduce infarct size (~47%) and to inhibit apoptosis (~60%) in the left ventricle of treated mice. Importantly, these effects are not observed following the injection of CPP alone or scrambled version of BH4. This study evidences that the Pip2b CPP, designed for oligonucleotides translocation, as well as the widely used natural Tat CPP exhibit similar efficacy in vivo to deliver BH4 anti-apoptotic peptide to the reperfused myocardium and may thus become useful therapeutic tools to treat acute myocardial infarction in the clinical setting.
Insights
New peptide conjugates show promise in protecting the heart from acute myocardial infarction. Tat-BH4 and Pip2b-BH4 significantly reduced heart damage and apoptosis in a mouse model, offering potential therapeutic strategies.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Myocardial ischemia-reperfusion (IR) injury significantly contributes to heart damage after acute myocardial infarction.
- Apoptosis is a key mechanism driving IR injury, necessitating cardioprotective pharmacological strategies.
Purpose of the Study:
- To evaluate the cardioprotective efficacy of cell-penetrating peptide (CPP)-conjugated BH4-peptide (CPP-BH4) in vitro and in vivo.
- To investigate the potential of Tat-BH4 and Pip2b-BH4 as therapeutic agents for acute myocardial infarction.
Main Methods:
- Developed four CPP-BH4 conjugates (Tat-BH4, (RXR)4-BH4, Bpep-BH4, Pip2b-BH4) using CPPs and the anti-apoptotic BH4-peptide.
- Assessed apoptosis reduction in primary cardiomyocytes treated with staurosporine.
- Evaluated infarct size and apoptosis in a mouse model of myocardial IR injury following intravenous administration of CPP-BH4 conjugates.
Main Results:
- CPP-BH4 conjugates reduced staurosporine-induced apoptosis in cardiomyocytes.
- A single low dose of Tat-BH4 and Pip2b-BH4 significantly reduced infarct size by ~47% and inhibited apoptosis by ~60% in the mouse left ventricle.
- Cardioprotective effects were specific to CPP-BH4 conjugates, as CPPs alone or scrambled BH4 showed no benefit.
Conclusions:
- The Pip2b and Tat CPPs effectively deliver the anti-apoptotic BH4-peptide to the myocardium.
- Tat-BH4 and Pip2b-BH4 demonstrate significant cardioprotective potential in vivo, reducing myocardial damage and apoptosis.
- These CPP-BH4 conjugates represent promising therapeutic tools for treating acute myocardial infarction in clinical settings.
