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Updated: Feb 22, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity
Stefania Caso1, Darko Maric2, Miroslav Arambasic2
1Département de Pharmacologie et de Toxicologie, Faculté de Biologie et de Médecine, Lausanne 1005, Switzerland; Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università di Bari, Via Orabona 4, 70125 Bari, Italy.
Abstract:
Doxorubicin (DOX) is a chemotherapic agent that is widely used to treat hematological and solid tumors. Despite its efficacy, DOX displays significant cardiac toxicity associated with cardiomyocytes death and heart failure. Cardiac toxicity is mainly associated with the ability of DOX to alter mitochondrial function. The current lack of treatments to efficiently prevent DOX cardiotoxicity underscores the need of new therapeutic approaches. Our current findings show that stimulation of cardiomyocytes with the α1-adrenergic receptor (AR) agonist phenylephrine (PE) significantly inhibits the apoptotic effect of DOX. Importantly, our results indicate that AKAP-Lbc is critical for transducing protective signals downstream of α1-ARs. In particular, we could show that suppression of AKAP-Lbc expression by infecting primary cultures of ventricular myocytes with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly impairs the ability of PE to reduce DOX-induced apoptosis. AKAP-Lbc-mediated cardiomyocyte protection requires the activation of anchored protein kinase D1 (PKD1)-dependent prosurvival pathways that promote the expression of the anti-apoptotic protein Bcl2 and inhibit the translocation of the pro-apoptotic protein Bax to mitochondria. In conclusion, AKAP-Lbc emerges as a coordinator of signals that protect cardiomyocytes against the toxic effects of DOX.
Insights
Phenylephrine (PE) protects heart cells from chemotherapy drug Doxorubicin (DOX) by activating AKAP-Lbc. This protein is crucial for preventing DOX-induced heart cell death and dysfunction.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug but causes significant cardiotoxicity, leading to heart failure.
- DOX-induced cardiotoxicity is linked to mitochondrial dysfunction and cardiomyocyte apoptosis.
- Current strategies to prevent DOX cardiotoxicity are limited, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the protective role of phenylephrine (PE) against Doxorubicin (DOX)-induced cardiotoxicity.
- To elucidate the involvement of AKAP-Lbc in mediating the cardioprotective effects of PE.
- To identify the downstream signaling pathways involved in AKAP-Lbc-mediated protection.
Main Methods:
- Primary cultures of ventricular myocytes were used.
- Phenylephrine (PE) was employed to stimulate α1-adrenergic receptors (ARs).
- Lentiviral vectors encoding AKAP-Lbc specific short hairpin RNAs (shRNAs) were used to suppress AKAP-Lbc expression.
- Apoptosis, mitochondrial translocation of Bax, and expression of Bcl2 were assessed.
Main Results:
- PE stimulation significantly inhibited DOX-induced apoptosis in cardiomyocytes.
- Suppression of AKAP-Lbc expression abolished the protective effect of PE against DOX toxicity.
- AKAP-Lbc-mediated protection involved the activation of protein kinase D1 (PKD1)-dependent prosurvival pathways.
- These pathways promoted Bcl2 expression and inhibited Bax translocation to mitochondria.
Conclusions:
- AKAP-Lbc plays a critical role in transducing cardioprotective signals downstream of α1-ARs.
- AKAP-Lbc coordinates signaling pathways that protect cardiomyocytes from Doxorubicin-induced apoptosis.
- Targeting AKAP-Lbc may represent a novel therapeutic strategy to prevent chemotherapy-induced cardiotoxicity.
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