title: Carvedilol enhances mesenchymal stem cell therapy for myocardial infarction via inhibition of caspase-3 expression.
abstract: Adult stem cells have shown great promise toward repairing infarcted heart and restoring cardiac function. Mesenchymal stem cells (MSCs), because of their inherent multipotent nature and their ability to secrete a multitude of growth factors and cytokines, have been used for cardiac repair with encouraging results. Preclinical studies showed that MSCs injected into infarcted hearts improve cardiac function and attenuate fibrosis. Although stem cell transplantation is a promising therapeutic option to repair the infarcted heart, it is faced with a number of challenges, including the survival of the transplanted cells in the ischemic region, due to excessive oxidative stress present in the ischemic region. The objective of this study was to determine the effect of Carvedilol (Carv), a nonselective β-blocker with antioxidant properties, on the survival and engraftment of MSCs in the infarcted heart. MSCs were subjected to a simulated host-tissue environment, similar to the one present in the infarcted myocardium, by culturing them in the presence of hydrogen peroxide (H(2)O(2)) to induce oxidative stress. MSCs were treated with 2.5 μM Carv for 1 h in serum-free medium, followed by treatment with H(2)O(2) for 2 h. The treated cells exhibited significant protection against H(2)O(2)-induced cell death versus untreated controls as determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays. Likewise, transplantation of MSCs after permanent left coronary artery ligation and treatment of animals after myocardial infarction (MI) with Carv (5 mg/kg b.wt.) led to significant improvement in cardiac function, decreased fibrosis, and caspase-3 expression compared with the MI or MSC-alone groups.
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors: Fatemat
authors: F
authors: Hassan
authors: Sarath
authors: S
authors: Meduru
authors: Kazuaki
authors: K
authors: Taguchi
authors: M Lakshmi
authors: ML
authors: Kuppusamy
authors: Mahmoud
authors: M
authors: Mostafa
authors: Periannan
authors: P
authors: Kuppusamy
authors: Mahmood
authors: M
authors: Khan
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000077261:Carvedilol; D053148:Caspase 3 / Q000096:biosynthesis*; D061945:Caspase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000502:physiology; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002227:Carbazoles; D061945:Caspase Inhibitors; D011412:Propanolamines; D000077261:Carvedilol; D053148:Caspase 3