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

Abstract

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.

Remote Ischemic Preconditioning and Renoprotection

“…11 The current concept of signal transduction in IPC suggests activation of the signaling cascades through the phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase (NOS)/cyclic guanosine monophosphate/PKG pathways, eventually leading to the opening of the ATP-dependent mitochondrial potassium (K ATP ) channel, which is believed to be a downstream target of PKG/PKC activation. 10,12,13 The activated mitochondrial K ATP channels have the ability to limit the opening of mitochondrial permeability transition pores, thus causing a marked improvement in cell survival. 14 Nitric oxide (NO) is emerging as an important cytoprotective agent and may play a pivotal role in rIPC both as a trigger and mediator of rIPC.…”

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

“…The ERK MAPK family, which consists of p44 and p42 isoforms, is activated by various stimuli, including oxidative stress and several G protein-coupled receptor agonists (19). There are numerous reports of ERK activation in cardiac tissue (4,6,7,15,21,23,24,26,32,(33)(34)(35)(36)(37), including in vivo evidence that ischemic PC and ␦-opioid PC activate at least one ERK isoform (7,24). Adenosine receptor subtypes, including the A 1 and A 2a receptors, have been reported to couple to the ERK pathway in both cardiac and noncardiac tissues (8,25,29).…”

Cardioprotective effects of KATP channel activation during hypoxia in goldfish Carassius auratus

“…Recent evidence suggests that NO/cGMP-dependent cardioprotection involves mitoK ATP channels, not as an endeffector, but as an element in a cascade of events leading to the production of reactive oxygen species (ROS; Lebuffe et al, 2003;Qin et al, 2004;Xu et al, 2004).…”