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1 Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: zxu{at}aims.unc.edu.
The purpose of this study was to test whether cGMP-dependent protein kinase (PKG) and mitochondrial KATP channels are involved in the exogenous NO donor S-nitroso-Nacetylpenicillamine (SNAP)-induced ROS generation. We also aimed to determine if extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3-kinase) are implicated in the action of SNAP. Rat cardiomyocytes treated with SNAP (20 µM) showed a significant increase in ROS generation. This increase was suppressed by both the selective blocker of mitochondrial KATP channels 5-hydroxydecanoate (5HD) and the non-selective KATP channel blocker glibenclamide. Direct opening of mitochondrial KATP channels with diazoxide leaded to ROS generation. The increased ROS generation was completely reversed by N-(2-mercaptopropionyl) glycine (MPG), a scavenger of ROS. Myxothiazol, an inhibitor of mitochondrial electron transport, also partially suppressed the ROS generation by SNAP. KT5823, an inhibitor of PKG, prevented SNAP-induced ROS generation indicating that activation of PKG is required for ROS generation. The involvement of PKG in SNAP-induced ROS generation was further supported by another experiment in which 8-Br-cGMP, an activator of PKG, significantly increased ROS generation. The effect of 8-Br-cGMP on ROS generation was reversed by either 5HD or MPG. YC-1, an activator of guanylyl cyclase (GC), also significantly increased ROS production, which was reversed by 5HD. Either LY294002 or wortmannin, the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), did not affect SNAPinduced ROS generation. In whole heart study, pretreatment with 10 µM SNAP significantly reduced infarct size in isolated rat hearts. The anti-infarct effect of SNAP was abrogated by either MPG or 5HD. The anti-infarct effect of SNAP was blocked by PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, but not by LY294002. Western blotting study showed that SNAP significantly enhanced phosphorylation of ERK. The increased phospho-ERK activities were reversed by MPG. These results strongly suggest that SNAP-induced ROS generation was mediated by activation of PKG and mitochondrial KATP channels and that opening of mitochondrial KATP channels is the downstream event of GC and PKG activation that causes ROS production. In addition, ROS and mitochondrial KATP channels participate in the anti-infarct effect of SNAP. Moreover, phosphorylation of ERK is the downstream signaling event of ROS production and plays an important role in the cardioprotective effect triggered by SNAP.
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