We hypothesized that inhibition of the cGMP-specific enzyme phosphodiesterase 5A (PDE5A) promoted cGMP/protein kinase G (PKG) activity to condition stem cells for enhanced survival and proliferation. One-time tadalafil treatment (1 μM for 30 min) of mesenchymal stem cells ( TadaMSCs) provided sustained protection of cells for 36 h. Higher cGMP activity with concomitantly increased PKG1 activity was observed in TadaMSCs, which peaked within 12 h after tadalafil treatment. Pretreatment with PKG1 blockers (1 μM KT-5823 or 20 nM K-252a) or transduction with adenoviral PKG1-short-hairpin RNA abolished tadalafil-induced cytoprotection of the cells. A higher proliferation rate was observed in TadaMSCs compared with nontreated MSCs ( ContMSCs). In a rat model of acute myocardial infarction, TadaMSCs transplanted 0 and 24 h after tadalafil treatment showed higher survival compared with ContMSCs on day 2 and day 4 after engraftment. TadaMSCs transplanted 48 h after tadalafil treatment lost their protection on both day 2 and day 4 after engraftment, and their rate of survival was similar to ContMSCs. Reduced terminal dUTP nick end-labeling positivity (P < 0.01 vs. ContMSCs) and higher proliferation of TadaMSCs (P < 0.01 vs. ContMSCs) was observed in the infarcted heart. Fluorescence immunostaining revealed neomyogenesis in both the infarct and peri-infarct areas. Blood vessel density was significantly increased in group 2 compared with group 1. Transthoracic echocardiographic heart function revealed significant preservation of the indexes of left ventricle contractility and attenuation of remodeling in TadaMSC-engrafted animal hearts (group 2) compared with ContMSCs (group 1). PDE5A inhibition using long-acting tadalafil is an innovative approach to promote stem cell survival and proliferation in the infarcted heart.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|State||Published - Nov 1 2010|
- Stem cells
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)