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Cardiovascular Research Advance Access first published online on August 21, 2009
This version [Corrected Proof] published online on September 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp289
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Native and reconstituted HDL protect cardiomyocytes from doxorubicin-induced apoptosis

Miguel A. Frias, Ursula Lang, Christine Gerber-Wicht and Richard W. James*

Faculty of Medicine, University of Geneva, Service of Endocrinology, Diabetology, and Nutrition, University Hospital, 4, rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland

* Corresponding author. Tel: +41 22 3729304, Fax: +41 22 3729329, Email: richard.james{at}hcuge.ch

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.

KEYWORDS HDL; Oxidative stress; Signalling pathways; Cardiomyopathies; Apolipoprotein AI

Time for primary review: 34 days


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