Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

Abstract

short hairpin rna therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol 302: H2112-H2121, 2012. First published March 23, 2012 doi:10.1152 doi:10. /ajpheart.00339.2011 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.

Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair

“…; Li et al. ; Kumar and Ashraf ). VASP downstream of PKG1 may be involved in the intracellular signaling pathways.…”

“…; Li et al. ); the mechanisms underlying tadalafil's effects on stem cell survival in vivo are incompletely understood. In this study, we attempt to define the novel pathways by which tadalafil treatment leads to cardioprotection.…”

Cardiac Role of Cyclic-GMP Hydrolyzing Phosphodiesterase Type 5: From Experimental Models to Clinical Trials

“…Though in vitro gene-deletion studies have supported specificity and selectivity for PDE5, attempts to generate in vivo PDE5 knockout models have been repeatedly unsuccessful. However, a new study [50] used small interfering RNA (siRNA) against PDE5 delivered intramyocardially by adenovirus and found improved cardiac remodeling postinfarction, with enhanced cGMP/PKG signaling. Furthermore, studies have utilized the more selective tadalafil reporting similar efficacy.…”

Protein Kinase G1 α Overexpression Increases Stem Cell Survival and Cardiac Function after Myocardial Infarction

“…Treatment with PDE-5 inhibitors, sildenafil or tadalafil, effected cardioprotection both in vitro and in vivo through PKG1 [27], [28], [29]. In a previous study we showed that PDE5a inhibition with adenoviral short hairpin RNA could protect cardiomyocytes against anoxia, attenuate infarction size and improve cardiac remodeling and dysfunction [30].…”