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 (H2O2) to induce oxidative stress. MSCs were treated with 2.5 μM Carv for 1 h in serum-free medium, followed by treatment with H2O2 for 2 h. The treated cells exhibited significant protection against H2O2-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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [Grant R01-EB006153] (to P.K.); and the American Heart Association [Grant SDG 0930181N] (to M.K.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- MSC
- mesenchymal stem cell
- ROS
- reactive oxygen species
- LAD
- left anterior descending
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- DEPMPO
- 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide
- MI
- myocardial infarction
- Carv
- Carvedilol
- PBS
- phosphate-buffered saline
- MTT
- 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide
- DAPI
- 4,6-diamidino-2-phenylindole
- α-SMA
- α-smooth muscle actin
- vWF
- von Willebrand factor
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- AMI
- acute MI
- BrdU
- 5-bromo-2′-deoxyuridine
- EPR
- electron paramagnetic resonance.
- Received May 26, 2012.
- Accepted June 26, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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