Activation of c-Jun N-Terminal Kinases and p38-Mitogen-activated Protein Kinases in Human Heart Failure Secondary to Ischaemic Heart Disease

Cook, Stuart A.; Sugden, Peter H.; Clerk, Angela

doi:10.1006/jmcc.1999.0979

Cited by 194 publications

(112 citation statements)

References 64 publications

(134 reference statements)

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“…Cell survival and death relies on the balance of pro-and anti-apoptotic proteins (57). Increases in BAD protein levels with parallel decreases in anti-apoptotic Bcl-2 in isolated porcine lung endothelial cells was shown to be sufficient for apoptosis induction (58).…”

Section: Pkc␦ Activation During Reperfusion Affects Bad Proteinmentioning

confidence: 99%

Protein Kinase Cδ Activation Induces Apoptosis in Response to Cardiac Ischemia and Reperfusion Damage

Murriel

Churchill

Inagaki

et al. 2004

Journal of Biological Chemistry

184

148

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Heart attacks caused by occlusion of coronary arteries are often treated by mechanical or enzymatic removal of the occlusion and reperfusion of the ischemic heart. It is now recognized that reperfusion per se contributes to myocardial damage, and there is a great interest in identifying the molecular basis of this damage. We recently showed that inhibiting protein kinase C␦ (PKC␦) protects the heart from ischemia and reperfusion-induced damage. Here, we demonstrate that PKC␦ activity and mitochondrial translocation at the onset of reperfusion mediates apoptosis by facilitating the accumulation and dephosphorylation of the pro-apoptotic BAD (Bcl-2-associated death promoter), dephosphorylation of Akt, cytochrome c release, PARP (poly(ADPribose) polymerase) cleavage, and DNA laddering. Our data suggest that PKC␦ activation has a critical proapoptotic role in cardiac responses following ischemia and reperfusion.

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Section: Pkc␦ Activation During Reperfusion Affects Bad Proteinmentioning

confidence: 99%

Protein Kinase Cδ Activation Induces Apoptosis in Response to Cardiac Ischemia and Reperfusion Damage

Murriel

Churchill

Inagaki

et al. 2004

Journal of Biological Chemistry

184

148

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“…The most extensively studied members of the MAPKs are extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK) (93). In cardiomyocytes, MAPK activation has been linked to a wide array of cellular events, including apoptosis (94,95), ischemia/reperfusion injury (96), and ischemic heart failure (97). It remains to be determined if myocardial MAPK activation also occurs during sepsis (Figure 1), and if MAPKs are also engaged in other myocardial defects like disturbance of sarcoplasmic calcium flux, etc.…”

Section: Mapk Signaling Cascadesmentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

107

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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“…2 ERKs are mainly involved in mediating anabolic processes such as cell division, growth, and differentiation; the JUN kinases and the p38 MAPK are generally associated with cellular response to diverse stresses. The clinical relevance of protein kinases in adult humans was recently demonstrated by an increased activity of JUN kinase and p38 MAPK in heart failure secondary to ischemic heart disease 3 and during cardiopulmonary bypass. 4 However, the role of PKC and MAPKs in the mechanisms by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia are unknown.…”

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confidence: 99%

Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts

et al. 2002

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Background-Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown. Method and Results-We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (SaO 2 Ͻ85%) or acyanotic (SaO 2 Ͼ95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (SaO 2 Ͻ85%) or normoxic (SaO 2 Ͼ95%) environment. Tissues from infant human and rabbit hearts were processed for Western and in vitro kinase analysis. In human infants with cyanotic heart defects, PKC⑀, p38 MAP kinase, and JUN kinase but not p42/44 MAP kinase were activated and translocated from the cytosolic to the particulate fraction compared with acyanotic heart defects. In rabbit infants there was a parallel response for PKC⑀, p38 MAP kinase, and JUN kinase similar to humans. In infant rabbit hearts inhibition of PKC⑀ with chelerythrine, p38 MAP kinase, with SB203580 and JUN kinase with curcumin abolished the cardioprotective effects of chronic hypoxia but had no effects on normoxic hearts. Conclusions-Infant human and rabbit hearts adapt to chronic hypoxia through activation of PKC⑀, p38 MAP kinase, and JUN kinase signal transduction pathways. These pathways may be responsible for cardioprotection in the chronically hypoxic infant rabbit heart. (Circulation. 2002;106:239-245.)

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Activation of c-Jun N-Terminal Kinases and p38-Mitogen-activated Protein Kinases in Human Heart Failure Secondary to Ischaemic Heart Disease

Cited by 194 publications

References 64 publications

Protein Kinase Cδ Activation Induces Apoptosis in Response to Cardiac Ischemia and Reperfusion Damage

Protein Kinase Cδ Activation Induces Apoptosis in Response to Cardiac Ischemia and Reperfusion Damage

Molecular Events in the Cardiomyopathy of Sepsis

Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts

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