A peptide inhibitor of c-Jun NH<sub>2</sub>-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo

Milano, Giuseppina; Morel, Sandrine; Bonny, Christophe; Samaja, Michele; Segesser, Ludwig K. von; Nicod, Pascal; Vassalli, Giuseppe

doi:10.1152/ajpheart.01117.2006

Cited by 100 publications

(101 citation statements)

References 30 publications

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“…Whether stress-induced JNK signaling has a protective or pathological effect depends on the cell type, a dichotomy that is apparent in cardiomyocytes. Treatment with JNK-specific inhibitors reduces infarct size and apoptotic cell death following IR [59,60]. JNK activity also exacerbates the deleterious effects of several proteins involved in IR-induced myocardial injury [60][61][62].…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with JNK-specific inhibitors reduces infarct size and apoptotic cell death following IR [59,60]. JNK activity also exacerbates the deleterious effects of several proteins involved in IR-induced myocardial injury [60][61][62]. Moreover, JNK is thought to associate with mitochondria, possibly via interactions with pro-apoptotic proteins [62], while it also regulates nuclear translocation of the mitochondrial apoptosis-inducing factor (AIF) [61,63].…”

Section: Discussionmentioning

confidence: 99%

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SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

Becatti

Taddei

Cecchi

et al. 2012

Cell. Mol. Life Sci.

129

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SIRT1, an ubiquitous NAD(?)-dependent deacetylase that plays a role in biological processes such as longevity and stress response, is significantly activated in response to reactive oxygen species (ROS) production. Resveratrol (Resv), an important activator of SIRT1, has been shown to exert major health benefits in diseases associated with oxidative stress. In ischemia-reperfusion (IR) injury, a major role has been attributed to the mitogenactivated protein kinase (MAPK) pathway, which is upregulated in response to a variety of stress stimuli, including oxidative stress. In neonatal rat ventricular cardiomyocytes subjected to simulated IR, the effect of Resv-induced SIRT1 activation and the relationships with the MAPK pathway were investigated. Resv-induced SIRT1 overexpression protected cardiomyocytes from oxidative injury, mitochondrial dysfunction, and cell death induced by IR. For the first time, we demonstrate that SIRT1 overexpression positively affects the MAPK pathway-via Akt/ASK1 signaling-by reducing p38 and JNK phosphorylation and increasing ERK phosphorylation. These results reveal a new protective mechanism elicited by Resv-induced SIRT1 activation in IR tissues and suggest novel potential therapeutic targets to manage IR-induced cardiac dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

Becatti

Taddei

Cecchi

et al. 2012

Cell. Mol. Life Sci.

129

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“…Although inhibition of JNK using a peptide inhibitor (25) or a nonpeptide ATP-competitive inhibitor (9) protected the myocardium against ischemia-reperfusion injury, both genetic inhibition and activation of JNK1/2 within the heart in mice protected the myocardium from ischemia-reperfusion-induced cell death in vivo (15). Moreover, activation of JNK has been shown to promote survival of cardiac myocytes after oxidative stress (7) and be cytoprotective during nitric oxide-induced cardiac myocyte apoptosis (1).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms underlying this phenomenon remain unclear. During the ischemia-reperfusion process, many kinases within the ischemic area are activated, including extracellular signal-regulated kinase (ERK)1/2, c-Jun NH 2 -terminal kinase (JNK)1/2, and p38 mitogen-activated protein kinase (p38 MAPK) (2,22,25). p38 MAPK, a stress-activated serine/threonine protein kinase belonging to the MAPK superfamily, plays a major role in regulating apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization (36).…”

mentioning

confidence: 99%

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

Chai¹,

Wu²,

Li³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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. Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 294: E183-E189, 2008. First published November 14, 2007 doi:10.1152/ajpendo.00571.2007.-Myocardial ischemiareperfusion injury contributes significantly to morbidity and mortality in patients with diabetes. Insulin decreases myocardial infarct size in animals and the rate of apoptosis in cultured cells. Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. A euglycemic clamp (3 mU ⅐ min Ϫ1 ⅐ kg Ϫ1 ) was begun either 10 min before ischemia (Insulin BI), 5 min before reperfusion (InsulinBR), or 30 min after the onset of reperfusion (Insulin AR ), and continued until the end of the study. Compared with saline control, insulin decreased the infarct size in both Insulin BI (P Ͻ 0.001) and InsulinBR (P Ͻ 0.02) rats but not in Insulin AR rats. The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. However, it completely abolished insulin's protective effect in Insulin BI and InsulinBR rats. Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in Insulin AR rats. We conclude that insulin protects myocardium against ischemiareperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect.

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“…64 This cell-permeable, protease-resistant peptide was also effective in reducing ischemic injury size by 50%, and enhancing post-ischemic cardiac function by impairing apoptosis in isolated-reperfused rat hearts. 65 Some of these results have been reviewed recently. 66 An interesting basic consideration put forward by analyzing the effects of these peptide inhibitors has emerged, namely the concept that interactions with specific subsets of substrates can be specifically targeted.…”

Section: Novel Implications Of Mapk Docking Interactionsmentioning

confidence: 99%

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Mayor¹,

Jurado-Pueyo²,

Campos³

et al. 2007

Cell Cycle

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A peptide inhibitor of c-Jun NH₂-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo

Abstract: Milano G, Morel S, Bonny C, Samaja M, von Segesser LK, Nicod P, Vassalli G. A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo.

Cited by 100 publications

References 30 publications

SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

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