Abstract
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-1α, 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.
Footnotes
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This work was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [Grants R01-EB006153, R01-EB004031].
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S.W. and M.K. contributed equally to this work.
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doi:10.1124/jpet.109.150839.
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ABBREVIATIONS: MI, myocardial infarction; MSC, mesenchymal stem cell; TMZ, trimetazidine, 1-[2,3,4-trimethoxybenzyl]piperazine; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; LDH, lactate dehydrogenase; H2O2, hydrogen peroxide; PI, propidium iodide; OCR, oxygen consumption rate; EPR, electron paramagnetic resonance; pAkt, phosphorylated Akt; RT, reverse transcriptase; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LAD, left anterior descending (coronary artery); LV, left ventricle; EF, ejection fraction; FS, fractional shortening.
- Received January 12, 2009.
- Accepted February 12, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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