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Selective SERCA2a activator as a candidate for chronic heart failure therapy.
Martina Arici1, Shih-Che Hsu2, Mara Ferrandi3
1Department of Biotechnology and Biosciences, Università Degli Studi di Milano-Bicocca, P.Za Della Scienza 2, 20126, Milan, Italy.
Journal of Translational Medicine
|January 19, 2024
Summary
A new drug, compound 8, effectively improves heart failure by stimulating sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) activity. This mechanism-based therapy shows promise for chronic heart failure treatment with good tolerability.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) dysfunction is a key factor in heart failure (HF)-related diastolic dysfunction.
- SERCA2a stimulation presents a potential mechanism-based therapeutic strategy for HF.
- Existing treatments like Istaroxime and its metabolite PST3093 have limitations for chronic HF management.
Purpose of the Study:
- To characterize compound 8, a novel PST3093 derivative, for potential chronic oral heart failure treatment.
- To evaluate the efficacy and safety of compound 8 in restoring SERCA2a activity and improving cardiac function.
Main Methods:
- Compound 8's effects were assessed in streptozotocin-treated rats, a model of diastolic dysfunction.
- In vitro and in vivo studies evaluated SERCA2a stimulation, cardiac function via echocardiography, and electrophysiological effects.
- Acute and chronic administration routes (i.v. and oral) were investigated.
Main Results:
- Compound 8 enhanced SR Ca2+ compartmentalization in cardiac myocytes.
- In vivo studies demonstrated significant improvement in diastolic function following both acute and chronic administration.
- Compound 8 exhibited no adverse effects on cardiac electrical activity and showed good tolerability in mice.
Conclusions:
- Compound 8 demonstrates potential as a safe and selective oral therapeutic agent for chronic heart failure.
- Restoring SERCA2a activity via compound 8 offers a promising mechanism-based approach to heart failure treatment.
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