Abstract
BackgroundPrevious 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.MethodsMI 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.ResultsAs 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.ConclusionsLong-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.
Highlights
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
Cardiac fibrosis is a major factor of tissue remodeling during myocardial infarction (MI) recovery, heart failure, ischemia reperfusion injury, and in most cardiomyopathies [1]
A novel antifibrotic and cardiomyocyte protective therapy complementing hemodynamic effects is emerging, i.e., the long-term continuous use of phosphodiesterase 5 inhibitors (PDE5i) [8,9], based initially on the cardiac preconditioning exerted by nitric oxide and its main effector cGMP, presumably through inducible nitric oxide synthase [10,11]
Summary
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. The etiology, molecular/cellular pathology, progression, and impact on contractile tissue compliance of cardiac tissue fibrosis, resemble the fibrosis occurring in the arterial bed wall [2,3] and in vascular tissues such as the kidney, skeletal muscle, urogenital organs [4,5,6], and others, except for the cells that are affected and the functional outcomes. A novel antifibrotic and cardiomyocyte protective therapy complementing hemodynamic effects is emerging, i.e., the long-term continuous use of phosphodiesterase 5 inhibitors (PDE5i) [8,9], based initially on the cardiac preconditioning exerted by nitric oxide and its main effector cGMP, presumably through inducible nitric oxide synthase (iNOS) [10,11]
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