Abstract 10615: Ischemia/Reperfusion Injury Increases PDE5 Expression in the Heart Possibly Independent of Reactive Oxygen Species
Background: Inhibition of phosphodiesterase-5 (PDE5) protects against myocardial ischemia/reperfusion (I/R) injury. However, it remains uncertain how PDE5 expression and activity are modulated by I/R in the heart. The present study was designed to investigate the effect of I/R on cardiac PDE5 and the potential role of reactive oxygen species (ROS) in induction of PDE5.
Methods & Results: Adult male ICR mice underwent 30 min of coronary artery ligation with or without 24 hrs of reperfusion. Ventricular tissue samples were collected for assessing the protein expression and activity of PDE5 and phosphorylated VASP (pVASP) - a downstream target of protein kinase G and protein kinase A. Ischemia alone and I/R significantly increased expression and activity of PDE5 (Figure 1A-B) without affecting pVASP. Similar results were obtained in isolated hearts subjected to 30 min of global ischemia with or without 30 min of reperfusion in Langendorff mode ex vivo, in which both expression and activity of PDE5 were increased following ischemia alone and I/R (P<0.05; Figure 1C). Interestingly, the hearts receiving intracoronary infusion of 100 μM hydrogen peroxide (H2O2) did not affect PDE5 expression (Figure 1D) and activity but raised pVASP level. Both I/R and H2O2 caused significant cellular injury as indicated by the enhanced leakage of lactate dehydrogenase as compared with the controls. The phosphorylation levels of PDE5 were not affected by any of the stressors. Figure 1E summarizes the key findings.
Conclusion: For the first time, we show that cardiac ischemia or I/R can lead to a robust upregulation of PDE5, which may contribute to the pathogenic outcome of I/R injury. The PDE5 induction appears to be independent of ROS, which failed to alter PDE5 expression/activity in the absence of I/R. These results further validate PDE5 as an important therapeutic target for limiting cardiac I/R injury.
- Ischemia reperfusion
- Free radicals/Free-radical scavengers
- Cardioprotective drugs
- © 2013 by American Heart Association, Inc.