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CARDIOVASCULAR

Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression

Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio (S.W., M.K., M.L.K., I.K.M., S.M.C., B.K.R., B.C.S., P.K.); and Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary (K.H.)

Stem cell transplantation is a possible therapeutic option to repair ischemic damage to the heart. However, it is faced with a number of challenges including the survival of the transplanted cells in the ischemic region. The present study was designed to use stem cells preconditioned with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine; TMZ), a widely used anti-ischemic drug for treating angina in cardiac patients, to increase the rate of their survival after transplantation. Bone marrow-derived rat mesenchymal stem cells (MSCs) were subjected to a simulated host tissue environment by culturing them under hypoxia (2% O₂) and using hydrogen peroxide (H₂O₂) to induce oxidative stress. MSCs were preconditioned with 10 µM TMZ for 6 h followed by treatment with 100 µM H₂O₂ for 1 h and characterized for their cellular viability and metabolic activity. The preconditioned cells showed a significant protection against H₂O₂-induced loss of cellular viability, membrane damage, and oxygen metabolism accompanied by a significant increase in HIF-1, survivin, phosphorylated Akt (pAkt), and Bcl-2 protein levels and Bcl-2 gene expression. The therapeutic efficacy of the TMZ-preconditioned MSCs was evaluated in an in vivo rat model of myocardial infarction induced by permanent ligation of left anterior descending coronary artery. A significant increase in the recovery of myocardial function and up-regulation of pAkt and Bcl-2 levels were observed in hearts transplanted with TMZ-preconditioned cells. This study clearly demonstrated the potential benefits of pharmacological preconditioning of MSCs with TMZ for stem cell therapy for repairing myocardial ischemic damage.

Address correspondence to: Dr. Periannan Kuppusamy, Davis Heart and Lung Research Institute, Ohio State University, 420 W. 12th Avenue, Room 114, Columbus, OH 43210. E-mail: kuppusamy.1{at}osu.edu