title: Mitochondria-mediated cardioprotection by trimetazidine in rabbit heart failure.
abstract: Trimetazidine (TMZ) is used successfully for treatment of ischemic cardiomyopathy, however its therapeutic potential in heart failure (HF) remains to be established. While the cardioprotective action of TMZ has been linked to inhibition of free fatty acid oxidation (FAO) via 3-ketoacyl CoA thiolase (3-KAT), additional mechanisms have been suggested. The aim of this study was to evaluate systematically the effects of TMZ on calcium signaling and mitochondrial function in a rabbit model of non-ischemic HF and to determine the cellular mechanisms of the cardioprotective action of TMZ. TMZ protected HF ventricular myocytes from cytosolic Ca(2+) overload and subsequent hypercontracture, induced by electrical and ß-adrenergic (isoproterenol) stimulation. This effect was mediated by the ability of TMZ to protect HF myocytes against mitochondrial permeability transition pore (mPTP) opening via attenuation of reactive oxygen species (ROS) generation by the mitochondrial electron transport chain (ETC) and uncoupled mitochondrial nitric oxide synthase (mtNOS). The majority of ROS generated by the ETC in HF arose from enhanced complex II-mediated electron leak. TMZ inhibited the elevated electron leak at the level of mitochondrial ETC complex II and improved impaired activity of mitochondrial complex I, thereby restoring redox balance and mitochondrial membrane potential in HF. While TMZ decreased FAO by ~15%, the 3-KAT inhibitor 4-bromotiglic acid did not provide protection against palmitic acid-induced mPTP opening, indicating that TMZ effects were 3-KAT independent. Thus, the beneficial effect of TMZ in rabbit HF was not linked to FAO inhibition, but rather associated with reduced complex II- and uncoupled mtNOS-mediated oxidative stress and decreased propensity for mPTP opening.
authors: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612, USA. Elena_Dedkova@rush.edu
authors: Elena N
authors: EN
authors: Dedkova
authors: Lea K
authors: LK
authors: Seidlmayer
authors: Lothar A
authors: LA
authors: Blatter
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004579:Electron Transport; D006333:Heart Failure / Q000517:prevention & control*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D014292:Trimetazidine / Q000627:therapeutic use*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D000102:Acetyl-CoA C-Acyltransferase; D014292:Trimetazidine; D002118:Calcium
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