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Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial K_ATP channels, and ERK

Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina 27599

Submitted 16 September 2003 ; accepted in final form 2 December 2003

We examined whether cGMP-dependent protein kinase (PKG) and mitochondrial ATP-sensitive potassium (K_ATP) channels are involved in S-nitroso-N-acetyl penicillamine (SNAP)-induced reactive oxygen species (ROS) generation. SNAP significantly increased ROS generation in cardiomyocytes. This increase was suppressed by both 5-hydroxydecanoate (5-HD) and glibenclamide. Direct opening of mitochondrial K_ATP channels with diazoxide led to ROS generation. The increased ROS generation was reversed by N-(2-mercaptopropionyl)glycine (MPG), a scavenger of ROS. Myxothiazol partially suppressed the ROS generation. KT-5823, an inhibitor of PKG, prevented ROS generation, indicating that PKG is required for ROS generation. In addition, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), an activator of PKG, induced ROS generation. The effect of 8-BrcGMP was reversed by either 5-HD or MPG. YC-1, an activator of guanylyl cyclase, also increased ROS production, which was reversed by 5-HD. Neither LY-294002 nor wortmannin, the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), affected SNAP's action. In a whole heart study, SNAP significantly reduced infarct size. The anti-infarct effect of SNAP was abrogated by either MPG or 5-HD. This effect was also blocked by PD-98059, an ERK inhibitor, but not by LY-294002. A Western blotting study showed that SNAP significantly enhanced phosphorylation of ERK, which was reversed by MPG. These results suggest that SNAP-induced ROS generation is mediated by activation of PKG and mitochondrial K_ATP channels and that opening of mitochondrial K_ATP channels is the downstream event of PKG activation. ROS and mitochondrial K_ATP channels participate in the anti-infarct effect of SNAP. Moreover, phosphorylation of ERK is the downstream signaling event of ROS and plays a role in the cardioprotection of SNAP.

reactive oxygen species; guanylyl cyclase; cGMP-dependent protein kinase; mitochondrial ATP-sensitive potassium channel; extracellular signal-regulated kinase; phosphatidylinositol 3-kinase

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