Doxorubicin induces cardiomyocyte dysfunction via a p38 MAP kinase-dependent oxidative stress mechanism.
Doxorubicin, an anthracycline used for cancer therapy, is known to elicit an irreversible cardiotoxicity. Several mechanisms were postulated for its cardiac toxicity including generation of reactive oxygen species (ROS). This study was designed to determine the acute effect of doxorubicin on cardiac mechanical and intracellular Ca(2+) properties in isolated ventricular myocytes. Contractile properties of male adult rat ventricular myocytes were analyzed including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocity of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) transients and generation of ROS were measured with fura-2 and fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, respectively. Acute (5 min) incubation of myocytes with doxorubicin (10(-9)-10(-4)M) significantly prolonged TPS, TR(90) and intracellular Ca(2+) transient decay rate without affecting PS, +/-dL/dt, resting intracellular Ca(2+) levels and electrically triggered intracellular Ca(2+) rise. Interestingly, the doxorubicin-induced prolongation of TPS and TR(90) was ablated by treatment of the antioxidant Vitamin C (100 microM) or the p38 MAP kinase inhibitor SB203580 (10 microM). Both Vitamin C and SB203580 unmasked a doxorubicin-induced positive response in PS. Vitamin C itself enhanced basal +/-dL/dt, whereas, SB203580 unmasked a doxorubicin-induced positive response of +/-dL/dt. The doxorubicin-induced response of intracellular Ca(2+) transients was essentially unaffected by Vitamin C. The role of ROS in doxorubicin-induced cardiac contractile response was confirmed with the ability of doxorubicin to enhance ROS generation, which was prevented by Vitamin C and SB203580. These data provide evidence that doxorubicin impairs cardiac contractile property in single myocytes through an oxidative stress-mediated pathway.
Wold
Loren E
LE
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
Aberle
Nicholas S
NS
Ren
Jun
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000633:toxicity*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium