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

Sheik Wisel, Mahmood Khan, M. Lakshmi Kuppusamy, I. Krishna Mohan, Simi M. Chacko, Brian K. Rivera, Benjamin C. Sun, Kálmán Hideg, Periannan Kuppusamy

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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% O 2) and using hydrogen peroxide (H 2O 2) to induce oxidative stress. MSCs were preconditioned with 10 M TMZ for 6 h followed by treatment with 100 μM H 2O 2 for 1 h and characterized for their cellular viability and metabolic activity. The preconditioned cells showed a significant protection against H 2O 2-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.

Original languageEnglish
Pages (from-to)543-550
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number2
DOIs
Publication statusPublished - May 1 2009

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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