Native and reconstituted HDL protect cardiomyocytes from doxorubicin-induced apoptosis.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Frias
Miguel A
MA
University of Geneva, Service of Endocrinology, Diabetology, and Nutrition, University Hospital, CH-1211 Geneva 14, Switzerland.
Lang
Ursula
U
Gerber-Wicht
Christine
C
James
Richard W
RW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C060506:sphingosine 1-phosphate; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine