Inhibition of c‐Jun N‐terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats

Ferrandi, Chiara; Ballerio, Rossana; Gaillard, P.; Giachetti, C; Carboni, Susanna; Vitte, Pierre-Alain; Gotteland, Jean‐Pierre; Cirillo, R

doi:10.1038/sj.bjp.0705873

Cited by 139 publications

(102 citation statements)

References 24 publications

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“…Through the use of a newly developed JNK-selective inhibitor or antisense oligoes, JNK activity was shown to play an important role in myocyte apoptosis after ischemia/reperfusion. 91,92 In contrast, a number of other studies demonstrated a critical role for JNK in myocyte survival and cardioprotection. 89 96,97 However, other prosurvival pathways, including AKT, also are targeted by JNK.…”

Section: Jnk Pathway In Cardiomyocyte Death Regulationmentioning

confidence: 82%

Mitogen-Activated Protein Kinases in Heart Development and Diseases

2007

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Abstract-Mitogen-activated protein (MAP) kinases belong to a highly conserved family of Ser-Thr protein kinases in the human kinome and have diverse roles in broad physiological functions. The 4 best-characterized MAP kinase pathways, ERK1/2, JNK, p38, and ERK5, have been implicated in different aspects of cardiac regulation, from development to pathological remodeling. Recent advancements in the development of kinase-specific inhibitors and genetically engineered animal models have revealed significant new insights about MAP kinase pathways in the heart. However, this explosive body of new information also has yielded many controversies about the functional role of specific MAP kinases as either detrimental promoters or critical protectors of the heart during cardiac pathological processes. These uncertainties have raised questions on whether/how MAP kinases can be targeted to develop effective therapies against heart diseases. In this review, recent studies examining the role of MAP kinase subfamilies in cardiac development, hypertrophy, and survival are summarized.

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Section: Jnk Pathway In Cardiomyocyte Death Regulationmentioning

confidence: 82%

Mitogen-Activated Protein Kinases in Heart Development and Diseases

2007

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“…Ischemia-reperfusion-Multiple studies have shown that pharmacological inhibition of JNK-1 reduces myocardial infarction and apoptosis in animal models of AMI (13,21,22,24). However, it is not possible to attribute an exclusive death-promoting role for JNK-1 because of other reports that JNK can be protective (20, 24 -27).…”

Section: Jnk-1 Protects Against Acute Injury During Briefmentioning

confidence: 91%

“…Akt regulates multiple survival pathways that collectively repress mitochondrial death channels and its inactivation by JNK after extended ischemia results in the loss of this protection. Inhibition of Akt by JNK-1 in this setting may account for as much as 50% of reperfusion-mediated infarction (21,22). When the period of ischemia is brief, ROS and kinase pathways are still activated by reperfusion, but ATP levels are maintained, and the role of JNK-1 is reversed.…”

Section: Jnk Protects Cardiac Myocytes Against Hypoxia Reoxygenation mentioning

confidence: 99%

c-Jun N-terminal Kinase (JNK-1) Confers Protection against Brief but Not Extended Ischemia during Acute Myocardial Infarction

Wei¹,

Wang²,

Chopra

et al. 2011

Journal of Biological Chemistry

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Brief periods of ischemia do not damage the heart and can actually protect against reperfusion injury caused by extended ischemia. It is not known what causes the transition from protection to irreversible damage as ischemia progresses. c-Jun N-terminal kinase-1 (JNK-1) is a stress-regulated kinase that is activated by reactive oxygen and thought to promote injury during severe acute myocardial infarction. Because some reports suggest that JNK-1 can also be protective, we hypothesized that the function of JNK-1 depends on the metabolic state of the heart at the time of reperfusion, a condition that changes progressively with duration of ischemia. Mice treated with JNK-1 inhibitors or transgenic mice wherein the JNK-1 gene was ablated were subjected to 5 or 20 min of ischemia followed by reperfusion. When JNK-1 was inactive, ischemia of only 5 min duration caused massive apoptosis, infarction, and negative remodeling that was equivalent to or greater than extended ischemia. Conversely, when ischemia was extended JNK-1 inactivation was protective. Mechanisms of the JNK-1 switch in function were investigated in vivo and in cultured cardiac myocytes. In vitro there was a comparable switch in the function of JNK-1 from protective when ATP levels were maintained during hypoxia to injurious when reoxygenation followed glucose and ATP depletion. Both apoptotic and necrotic death pathways were affected and responded reciprocally to JNK-1 inhibitors. JNK-1 differentially regulated Akt phosphorylation of the regulatory sites Ser-473 and Thr-450 and the catalytic Thr-308 site in vivo. The studies define a novel role for JNK-1 as a conditional survival kinase that protects the heart against brief but not protracted ischemia.There are more than 1,000,000 cases of acute myocardial infarction (AMI) 3 in the United States each year and many progress to heart failure (1, 2). Timely reperfusion by angioplasty, coronary artery bypass grafting, or thrombolytic therapy is the most effective treatment for limiting the extent of infarction and improving clinical outcome. However, reperfusion itself after protracted ischemia is known to cause additional irreversible injury (2). Myocardial infarction involves overlapping contributions of programmed death (apoptosis) and necrosis (3-5). During reperfusion, mitochondria are rapidly re-energized, and intracellular levels of reactive oxygen species (ROS) and calcium increase favoring an open state of mitochondrial death channels (3-8). Reperfusion also activates the so-called death and survival kinases that contribute importantly to cell fate and degree of infarction (reviewed in Refs. 1, 9 -11). When the heart is reperfused after a short period of ischemia, irreversible injury is avoided, and the consequences of ischemia reperfusion are limited to reversible defects of contractility known as myocardial stunning. Stunning is probably caused by elevations of reactive oxygen species (ROS) and calcium that are generated during reperfusion. Stunning varies in intensity, and although it usually r...

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“…By contrast, JNK inhibitors have been proposed to prevent cell death associated with stroke and myocardial infarction (21,46). It is also likely that JNK inhibition may prevent ischemia-induced edema, which has also been linked to abnormal VEGF production (47).…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Gumá

Rius

Duong-Polk

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Many ocular pathologies, including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration, result in vision loss because of aberrant neoangiogenesis. A common feature of these conditions is the presence of hypoxic areas and overexpression of the proangiogenic vascular endothelial growth factor (VEGF). The prevailing current treatment, laser ablation of the retina, is destructive and only partially effective. Preventive and less destructive therapies are much more desirable. Here, we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit reduced pathological angiogenesis and lower levels of retinal VEGF production in a murine model of ROP. We found that hypoxia induces JNK activation and regulates VEGF expression by enhancing the binding of phospho-c-Jun to the VEGF promoter. Intravitreal injection of a specific JNK inhibitor decreases retinal VEGF expression and reduces pathological retinal neovascularization without obvious side effects. These results strongly suggest that JNK1 plays a key role in retinal neoangiogenesis and that it represents a new pharmacological target for treatment of diseases where excessive neoangiogenesis is the underlying pathology.neoangiogenesis ͉ retinopathy of prematurity

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Inhibition of c‐Jun N‐terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats

Cited by 139 publications

References 24 publications

Mitogen-Activated Protein Kinases in Heart Development and Diseases

Mitogen-Activated Protein Kinases in Heart Development and Diseases

c-Jun N-terminal Kinase (JNK-1) Confers Protection against Brief but Not Extended Ischemia during Acute Myocardial Infarction

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

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