title: Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction.
abstract: We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45267-0529, USA.
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Husnain Kh
authors.initials: HKh
authors.lastname: Haider
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000150:complications* / Q000209:etiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D034741:RNA, Small Interfering; D012367:RNA, Viral; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006152:Cyclic GMP