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.
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 microM TMZ for 6 h followed by treatment with 100 microM 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-1alpha, 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.
Wisel
Sheik
S
Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
Khan
Mahmood
M
Kuppusamy
M Lakshmi
ML
Mohan
I Krishna
IK
Chacko
Simi M
SM
Rivera
Brian K
BK
Sun
Benjamin C
BC
Hideg
Kálmán
K
Kuppusamy
Periannan
P
D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014292:Trimetazidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D014665:Vasodilator Agents; D019938:Cyclin D1; D014292:Trimetazidine