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Updated: Jun 20, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Native and reconstituted HDL protect cardiomyocytes from doxorubicin-induced apoptosis
Miguel A Frias1, Ursula Lang, Christine Gerber-Wicht
1University of Geneva, Service of Endocrinology, Diabetology, and Nutrition, University Hospital, CH-1211 Geneva 14, Switzerland.
Insights
High-density lipoprotein (HDL) and its sphingosine-1-phosphate (S1P) component protect heart cells from doxorubicin toxicity. This finding may help reduce chemotherapy side effects by targeting specific anti-apoptotic pathways.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Doxorubicin is an effective anti-cancer drug but causes significant cardiotoxicity.
- High-density lipoprotein (HDL) has demonstrated protective effects on cardiomyocytes, particularly against oxidative stress.
Purpose of the Study:
- To investigate the impact of native and reconstituted HDL on doxorubicin-induced cardiomyocyte apoptosis.
- To elucidate the specific mechanisms and signaling pathways involved in HDL-mediated cardioprotection.
Main Methods:
- Neonatal rat ventricular cardiomyocytes were exposed to doxorubicin.
- Apoptosis was assessed via caspase-3 activation, DNA fragmentation, and cell viability assays.
- The roles of HDL, sphingosine-1-phosphate (S1P), S1P receptors, ERK1/2, and Stat3 were evaluated using various treatments and inhibitors.
Main Results:
- Both native and reconstituted HDL significantly reduced doxorubicin-induced cardiomyocyte apoptosis.
- The cardioprotective effect was primarily attributed to the S1P component of HDL, mediated via the S1P2 receptor.
- The extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Stat3 signaling pathways were essential for the anti-apoptotic actions of HDL and S1P.
Conclusions:
- HDL and its S1P component offer a promising strategy to mitigate doxorubicin-induced cardiotoxicity.
- Targeting the identified S1P2-ERK1/2-Stat3 anti-apoptotic pathway could enhance cardiomyocyte survival during doxorubicin therapy.
Aims:
We analysed the impact of native and reconstituted HDL on doxorubicin-induced cardiomyocyte apoptosis. While it is an effective anti-cancer agent, doxorubicin has serious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes, notably against oxidative stress.
Methods And Results:
Cultured neonatal rat ventricular cardiomyocytes were subjected to doxorubicin-induced stress, monitored as caspase3 activation, apoptotic DNA fragmentation and cell viability. The protective effects of HDL and sphingosine-1-phosphate (S1P) were investigated using native HDL, reconstituted HDL of varied composition and agonists and antagonists of S1P receptors. Anti-apoptotic signalling pathways were identified with specific inhibitors. Native and reconstituted HDL significantly decreased doxorubicin-induced cardiomyocyte apoptosis, essentially due to the S1P component of HDL. The latter was mediated by the S1P2 receptor, but not the S1P1 or S1P3 receptors. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signalling pathway was required for the anti-apoptotic effects of HDL and S1P. The transcription factor Stat3 also played an important role, as inhibition of its activity compromised the protective effects of HDL and S1P on doxorubicin-induced apoptosis.
Conclusion:
HDL and its sphingosine-1-phosphate component can protect cardiomyocytes against doxorubicin toxicity and may offer one means of reducing cardiotoxic side effects during doxorubicin therapy. The study identified anti-apoptotic pathways that could be exploited to improve cardiomyocyte survival.