Open Access Research

Effects of sildenafil and/or muscle derived stem cells on myocardial infarction

Judy SC Wang1, Istvan Kovanecz13, Dolores Vernet12, Gaby Nolazco12, George E Kopchok1, Sheryl L Chow4, Rodney A White1 and Nestor F Gonzalez-Cadavid123*

Author Affiliations

1 Department of Surgery, Los Angeles Biomedical Research Institute (LABioMed) at Harbor-UCLA Medical Center, Torrance, CA, USA

2 Department of Internal Medicine, Charles Drew University, Los Angeles, CA, USA

3 Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

4 Western University, Pomona, CA, USA

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Journal of Translational Medicine 2012, 10:159  doi:10.1186/1479-5876-10-159

Published: 7 August 2012

Abstract

Background

Previous studies have shown that long-term oral daily PDE 5 inhibitors (PDE5i) counteract fibrosis, cell loss, and the resulting dysfunction in tissues of various rat organs and that implantation of skeletal muscle-derived stem cells (MDSC) exerts some of these effects. PDE5i and stem cells in combination were found to be more effective in non-MI cardiac repair than each treatment separately. We have now investigated whether sildenafil at lower doses and MDSC, alone or in combination are effective to attenuate LV remodeling after MI in rats.

Methods

MI was induced in rats by ligature of the left anterior descending coronary artery. Treatment groups were: “Series A”: 1) untreated; 2) oral sildenafil 3 mg/kg/day from day 1; and “Series B”: intracardiac injection at day 7 of: 3) saline; 4) rat MDSC (106 cells); 5) as #4, with sildenafil as in #2. Before surgery, and at 1 and 4 weeks, the left ventricle ejection fraction (LVEF) was measured. LV sections were stained for collagen, myofibroblasts, apoptosis, cardiomyocytes, and iNOS, followed by quantitative image analysis. Western blots estimated angiogenesis and myofibroblast accumulation, as well as potential sildenafil tachyphylaxis by PDE 5 expression. Zymography estimated MMPs 2 and 9 in serum.

Results

As compared to untreated MI rats, sildenafil improved LVEF, reduced collagen, myofibroblasts, and circulating MMPs, and increased cardiac troponin T. MDSC replicated most of these effects and stimulated cardiac angiogenesis. Concurrent MDSC/sildenafil counteracted cardiomyocyte and endothelial cells loss, but did not improve LVEF or angiogenesis, and upregulated PDE 5.

Conclusions

Long-term oral sildenafil, or MDSC given separately, reduce the MI fibrotic scar and improve left ventricular function in this rat model. The failure of the treatment combination may be due to inducing overexpression of PDE5.

Keywords:
Stem cells; Myocardial infarction; Heart failure; PDE5 inhibitors; Fibrosis