Effect of mitochondrial ATP-sensitive potassium channel opening on the translocation of protein kinase C epsilon in adult rat ventricular myocytes

Li, H.; Yang, Tingting; Long, Zai-Yun; Ji, Cheng

doi:10.4238/2014.june.17.3

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…However, NNC 55-0462, another novel potassium channel opener, does not promote εPKC activation [ 34 ]. In rat ventricular myocytes, diazoxide, a mitoK ATP channel opener, induces εPKC translocation [ 35 ]. εPKC inhibitor cheleryhrine does not abolish infarct size-limiting effect of diazoxide in rabbit hearts, but it blocks the protective effect of diazoxide in rat myocardial infarction [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats

Zhang

Tian

Ying

et al. 2016

Cardiovasc Diabetol

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BackgroundDiabetic patients suffer from undesired intimal hyperplasia after angioplasty. Nicorandil has a trend to reduce the rate of target lesion revascularization. However, whether nicorandil inhibits intimal hyperplasia and the possible mechanisms underlying it remain to be determined. We aimed at assessing the effect of nicorandil on intimal hyperplasia in diabetic rats.MethodsAfter intraperitoneal injection of streptozotocin (STZ, 50 mg/kg), balloon injury model was established in carotid arteries of diabetic rats. Rats were randomized to vehicle, nicorandil (15 mg/kg/day) or 5-hydroxydecanoate (5-HD, 10 mg/kg/day), a mitochondrial ATP-sensitive potassium channel (mitoKATP channel)-selective antagonist. Perivascular delivery of εPKC siRNA was conducted to determine the role of εPKC pathway in intimal hyperplasia. In hyperglycemia environment (25 mM glucose), primary culture of vascular smooth muscle cells (VSMCs) were treated with nicorandil or 5-HD. Cell proliferation and cell migration were analyzed.ResultsIntimal hyperplasia significantly increased 14 days after balloon injury in diabetic rats (p < 0.01). Nicorandil inhibited intima development, reduced inflammation and prevented cell proliferation in balloon-injured arteries (p < 0.01). The protective effects of nicorandil were reversed by 5-HD (p < 0.05). εPKC was activated in balloon-injured arteries (p < 0.01). Nicorandil inhibited εPKC activation by opening mitoKATP channel. Perivascular delivery of εPKC siRNA inhibited intimal hyperplasia, inflammation and cell proliferation (p < 0.01). High glucose-induced VSMCs proliferation and migration were inhibited by nicorandil. εPKC activation induced by high glucose was also inhibited by nicorandil and that is partially reversed by 5-HD. εPKC knockdown prevented VSMCs proliferation and migration (p < 0.01).ConclusionsOur study demonstrates that nicorandil inhibits intimal hyperplasia in balloon-injured arteries in diabetic rats. Nicorandil also prevents VSMCs proliferation and migration induced by high glucose. The beneficial effect of nicorandil is conducted via opening mitoKATP channel and inhibiting εPKC activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0377-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats

Zhang

Tian

Ying

et al. 2016

Cardiovasc Diabetol

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“…In a study of myocytes, researchers observed that opening of mitoKATP channels may activate PKC ε and induce its translocation into myofibrillar-like structures. PKC ε activation occurs downstream of the mitoKATP channel, possibly as a result of ROS production after the opening of mitoKATP channels [ 30 ]. In the present study, we demonstrated that diazoxide can increase PKC ε expression but that this increase in expression is abrogated by 5-HD.…”

Section: Discussionmentioning

confidence: 99%

Diazoxide Attenuates Postresuscitation Brain Injury in a Rat Model of Asphyxial Cardiac Arrest by Opening Mitochondrial ATP-Sensitive Potassium Channels

Wang

et al. 2016

BioMed Research International

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Objective. We investigated whether and how diazoxide can attenuate brain injury after cardiopulmonary resuscitation (CPR) by selective opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels. Methods. Adult male Sprague-Dawley rats with induced cerebral ischemia (n = 10 per group) received an intraperitoneal injection of 0.1% dimethyl sulfoxide (1 mL; vehicle group), diazoxide (10 mg/kg; DZ group), or diazoxide (10 mg/kg) plus 5-hydroxydecanoate (5 mg/kg; DZ + 5-HD group) 30 min after CPR. The control group (sham group, n = 5) underwent sham operation, without cardiac arrest. Mitochondrial respiratory control rate (RCR) was determined. Brain cell apoptosis was assessed using TUNEL staining. Expression of Bcl-2, Bax, and protein kinase C epsilon (PKCε) in the cerebral cortex was determined by Western blotting and immunohistochemistry. Results. The neurological deficit scores (NDS) in the vehicle group decreased significantly at 24 h and 48 h after CPR. Diazoxide significantly improved NDS and mitochondrial RCR after CPR at both time points; 5-HD cotreatment abolished these effects. Diazoxide decreased TUNEL-positive cells following CPR, upregulated Bcl-2 and PKCε, downregulated Bax, and increased the Bcl-2/Bax ratio; 5-HD cotreatment reversed these effects. Conclusions. Diazoxide attenuates postresuscitation brain injury, protects mitochondrial function, inhibits brain cell apoptosis, and activates the PKC pathway by opening mitoKATP channels.

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“…Intriguingly, both AT 1 R and AT 2 R lack a subcellular targeting sequence (2), and whether they are bound to molecular chaperones and TOM70 (38) remains unknown. A translocation process, however, is supported by the inhibitory effect of chelerythrine, which reportedly inhibits the activation/translocation of PKC from the cytosol to subcellular or particulate fractions (3,57).…”

Section: Mitochondrial Angiotensin Receptors and Cardioprotectionmentioning

confidence: 99%

Mitochondrial angiotensin receptors and cardioprotective pathways

Escobales

Nuñez

Javadov

2019

American Journal of Physiology-Heart and Circulatory Physiology

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A growing body of data provides strong evidence that intracellular angiotensin II (ANG II) plays an important role in mammalian cell function and is involved in the pathogenesis of human diseases such as hypertension, diabetes, inflammation, fibrosis, arrhythmias, and kidney disease, among others. Recent studies also suggest that intracellular ANG II exerts protective effects in cells during high extracellular levels of the hormone or during chronic stimulation of the local tissue renin-angiotensin system (RAS). Notably, the intracellular RAS (iRAS) described in neurons, fibroblasts, renal cells, and cardiomyocytes provided new insights into regulatory mechanisms mediated by intracellular ANG II type 1 (AT1Rs) and 2 (AT2Rs) receptors, particularly, in mitochondria and nucleus. For instance, ANG II through nuclear AT1Rs promotes protective mechanisms by stimulating the AT2R signaling cascade, which involves mitochondrial AT2Rs and Mas receptors. The stimulation of nuclear ANG II receptors enhances mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thus protecting the cell against oxidative stress. Recent studies in ANG II-induced preconditioning suggest that plasma membrane AT2R stimulation exerts protective effects against cardiac ischemia-reperfusion by modulating mitochondrial AT1R and AT2R signaling. These studies indicate that iRAS promotes the protection of cells through nuclear AT1R signaling, which, in turn, promotes AT2R-dependent processes in mitochondria. Thus, despite abundant data on the deleterious effects of intracellular ANG II, a growing body of studies also supports a protective role for iRAS that could be of relevance to developing new therapeutic strategies. This review summarizes and discusses previous studies on the role of iRAS, particularly emphasizing the protective and counterbalancing actions of iRAS, mitochondrial ANG II receptors, and their implications for organ protection.

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Effect of mitochondrial ATP-sensitive potassium channel opening on the translocation of protein kinase C epsilon in adult rat ventricular myocytes

Cited by 8 publications

References 21 publications

Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats

Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats

Diazoxide Attenuates Postresuscitation Brain Injury in a Rat Model of Asphyxial Cardiac Arrest by Opening Mitochondrial ATP-Sensitive Potassium Channels

Mitochondrial angiotensin receptors and cardioprotective pathways

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