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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 329; no. 2; pp. 543 - 550
• Main Authors: Wisel, Sheik, Khan, Mahmood, Kuppusamy, M Lakshmi, Mohan, I Krishna, Chacko, Simi M, Rivera, Brian K, Sun, Benjamin C, Hideg, Kálmán, Kuppusamy, Periannan
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.2009
• Subjects: Animals; Blotting, Western; Cardiovascular; Cell Hypoxia - drug effects; Cell Survival - drug effects; Cyclin D1 - biosynthesis; Disease Models, Animal; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Myocardial Infarction - metabolism; Myocardial Infarction - therapy; Oxidative Stress - drug effects; Oxygen Consumption; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Trimetazidine - administration & dosage; Trimetazidine - pharmacology; Trimetazidine - therapeutic use; Vasodilator Agents - administration & dosage; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.150839

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