Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide

Sasaki, Norihito; Sato, Toshiaki; Ohler, Andreas; O’Rourke, Brian; Marbán, Eduardo

doi:10.1161/01.cir.101.4.439

Cited by 318 publications

(200 citation statements)

References 29 publications

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“…Indeed, several proteins involved in Ca 2+ and redox signaling are known to be modified by S-nitrosation, including L-type Ca 2+ channels [77], ryanodine receptors [78], thioredoxin [79] hemoglobin [80], mitochondrial K + ATP channels [81,82], TRP channels [83], and caspases [26]. The relative importance of complex I as a mediator of the cardioprotective effects of NO • remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Nadtochiy

Burwell

Brookes

2007

Journal of Molecular and Cellular Cardiology

132

118

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Mitochondrial dysfunction is a key pathologic event in cardiac ischemia-reperfusion (IR) injury, and protection of mitochondrial function is a potential mechanism underlying ischemic preconditioning (IPC). Acknowledging the role of nitric oxide (NO • ) in IPC, it was hypothesized that mitochondrial protein S-nitrosation may be a cardioprotective mechanism. The reagent S-nitroso-2-mercaptopropionyl-glycine (SNO-MPG) was therefore developed to enhance mitochondrial Snitrosation and elicit cardioprotection. Within cardiomyocytes, mitochondrial proteins were effectively S-nitrosated by SNO-MPG. Consistent with the recent discovery of mitochondrial complex I as an S-nitrosation target, SNO-MPG inhibited complex I activity and cardiomyocyte respiration. The latter effect was insensitive to the NO • scavenger c-PTIO, indicating no role for NO • -mediated complex IV inhibition. A cardioprotective role for reversible complex I inhibition has been proposed, and consistent with this SNO-MPG protected cardiomyocytes from simulated IR injury. Further supporting a cardioprotective role for endogenous mitochondrial S-nitrosothiols, patterns of protein S-nitrosation were similar in mitochondria isolated from Langendorff perfused hearts subjected to IPC, and mitochondria or cells treated with SNO-MPG. The functional recovery of perfused hearts from IR injury was also improved under conditions which stabilized endogenous S-nitrosothiols (i.e. dark), or by pre-ischemic administration of SNO-MPG. Mitochondria isolated from SNO-MPG-treated hearts at the end of ischemia exhibited improved Ca 2+ handling and lower ROS generation. Overall these data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation.

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Section: Discussionmentioning

confidence: 99%

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Nadtochiy

Burwell

Brookes

2007

Journal of Molecular and Cellular Cardiology

132

118

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“…The origin of these protective reactive species can be many, including mitochondria, in which K þ ATP (mK ATP ) channels, which are considered targets of protective cascades (14,142,161,168,201), may play a pivotal role. In fact, it has been suggested that mK ATP channel activation leads to alkalinization of the mitochondrial matrix and generation of ROS=RNS with a protective signaling role (33,142,168,201).…”

Section: Interaction Between Redox Environment and Cardioprotective Pmentioning

confidence: 99%

“…In fact, it has been suggested that mK ATP channel activation leads to alkalinization of the mitochondrial matrix and generation of ROS=RNS with a protective signaling role (33,142,168,201). It has also been suggested that NO donors activate mK ATP channels in rabbit ventricular myocytes and potentiate the protective effect of mK ATP opener diazoxide (168).…”

Section: Interaction Between Redox Environment and Cardioprotective Pmentioning

confidence: 99%

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Pagliaro

Moro

Tullio

et al. 2011

Antioxidants & Redox Signaling

114

152

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Post-ischemic reperfusion may result in reactive oxygen species (ROS) generation, reduced availability of nitric oxide (NO ), Ca 2+ overload, prolonged opening of mitochondrial permeability transition pore, and other processes contributing to cell death, myocardial infarction, stunning, and arrhythmias. With the discovery of the preconditioning and postconditioning phenomena, reperfusion injury has been appreciated as a reality from which protection is feasible, especially with postconditioning, which is under the control of physicians. Potentially cooperative protective signaling cascades are recruited by both pre-and postconditioning. In these pathways, phosphorylative= dephosphorylative processes are widely represented. However, cardioprotective modalities of signal transduction also include redox signaling by ROS, S-nitrosylation by NO and derivative, S-sulfhydration by hydrogen sulfide, and O-linked glycosylation with beta-N-acetylglucosamine. All these modalities can interact and regulate an entire pathway, thus influencing each other. For instance, enzymes can be phosphorylated and=or nitrosylated in specific and=or different site(s) with consequent increase or decrease of their specific activity. The cardioprotective signaling pathways are thought to converge on mitochondria, and various mitochondrial proteins have been identified as targets of these post-transitional modifications in both pre-and postconditioning. Antioxid. Redox Signal. 14, 833-850.

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“…In addition, a recent study in rabbits has shown that early translocation of protein kinase C, especially the ␣, , and ␦ isoforms to the membranous fractions, may play an essential role in sildenafil-induced cardioprotection (16). Based on these studies (13)(14)(15)(16), we postulated that sildenafil triggers signaling cascade that involves the activation of protein kinase C, the generation of NO, and the accumulation of cGMP in the myocardium through inducible and endothelial nitric-oxide synthase (iNOS and eNOS), thereby leading to cardioprotection via opening of mitochondrial ATP-sensitive potassium channels (17)(18)(19) .…”

mentioning

confidence: 99%

Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis

Das

Xi²,

Kukreja

2005

Journal of Biological Chemistry

323

276

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We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 M) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5 ,6,6 -tetrachloro-1,1 ,3,3 -tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.

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Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide

Abstract: NO directly activates mitoK(ATP) channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoK(ATP) channels.

Cited by 318 publications

References 29 publications

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis

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