Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin

Izem-Meziane M, Djerdjouri B, Rimbaud S, Caffin F, Fortin D, Garnier A, Veksler V, Joubert F, Ventura-Clapier R. Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin. Am J Physiol Heart Circ Physiol 302: H665-H674, 2012. First published November 18, 2011; doi:10.1152/ajpheart.00467.2011.-The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg . kg(-1) . day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg . kg(-1) . day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT-PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline-induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening.