Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151814 (coronary occlusion)
 3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that okadaic acid (OA), a known inhibitor of Ser/Thr phosphatases, protects pig myocardium against ischemic injury in an in vivo model and stimulates the activities of stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs). When OA was directly infused into the subsequently ischemic myocardium for 60 min before a 60-min period of coronary occlusion followed by reperfusion, infarct size was reduced from a control value of 83.4 +/- 2.8% of the risk region to 40.7 +/- 9.1%. When OA was infused for 10 min before a 5-min occlusion and during 45 min thereafter, infarct size was reduced to 26.5%. In a separate set of similar experiments, we pretreated pig hearts in vivo with the protein-synthesis inhibitor and known activator of SAPK/JNK, anisomycin (AN), and found that this compound also significantly reduced infarct size from 83.4 +/- 2.8.1% to 48.1 +/- 5.1%. For in vitro assays, OA (600 nM), AN (500 microM), or solvent (KHB) were locally infused into the left ventricular myocardium, and biopsies from in situ beating hearts were obtained after 10, 30, and 60 min of infusion. The activities of Ser/Thr phosphatases (PPases), especially PP-2A, were significantly decreased after OA infusion. OA infusion increased the activity (in-gel phosphorylation of N-terminal c-Jun1-135) of both 46- and 55-kDa SAPK/JNKs (twofold to threefold, 30 and 60 min of infusion), and this increase correlated well with the observed decrease of PPase activities. Western blot analysis with a phosphospecific SAPK/JNK (Thr 183/Tyr 185) antibody showed an increased content of the phosphorylated forms after OA treatment. We observed significant stimulation of SAPK/JNK activity also after AN treatment (threefold to fourfold, after 30 min of infusion). In contrast to the SAPK/JNKs, the infusion of both OA and AN did not significantly change the activities and phosphorylation of extracellular signal-related kinases (ERKs) and p38-MAPK. The findings that the protective effect of both OA and AN correlates with increased activity of SAPK/JNKs suggest the involvement of these enzymes in the mechanism of cardioprotection.
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PMID:Okadaic acid and anisomycin are protective and stimulate the SAPK/JNK pathway. 1044 68

Sphingosine 1-phosphate (S1P) is released at sites of tissue injury and effects cellular responses through activation of G protein-coupled receptors. The role of S1P in regulating cardiomyocyte survival following in vivo myocardial ischemia-reperfusion (I/R) injury was examined by using mice in which specific S1P receptor subtypes were deleted. Mice lacking either S1P(2) or S1P(3) receptors and subjected to 1-h coronary occlusion followed by 2 h of reperfusion developed infarcts equivalent to those of wild-type (WT) mice. However, in S1P(2,3) receptor double-knockout mice, infarct size following I/R was increased by >50%. I/R leads to activation of ERK, JNK, and p38 MAP kinases; however, these responses were not diminished in S1P(2,3) receptor knockout compared with WT mice. In contrast, activation of Akt in response to I/R was markedly attenuated in S1P(2,3) receptor knockout mouse hearts. Neither S1P(2) nor S1P(3) receptor deletion alone impaired I/R-induced Akt activation, which suggests redundant signaling through these receptors and is consistent with the finding that deletion of either receptor alone did not increase I/R injury. The involvement of cardiomyocytes in S1P(2) and S1P(3) receptor mediated activation of Akt was tested by using cells from WT and S1P receptor knockout hearts. Akt was activated by S1P, and this was modestly diminished in cardiomyocytes from S1P(2) or S1P(3) receptor knockout mice and completely abolished in the S1P(2,3) receptor double-knockout myocytes. Our data demonstrate that activation of S1P(2) and S1P(3) receptors plays a significant role in protecting cardiomyocytes from I/R damage in vivo and implicate the release of S1P and receptor-mediated Akt activation in this process.
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PMID:Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury. 1729 97

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that also modulates physiologic cell signaling pathways. MIF is expressed in cardiomyocytes and limits cardiac injury by enhancing AMPK activity during ischemia. Reperfusion injury is mediated in part by activation of the stress kinase JNK, but whether MIF modulates JNK in this setting is unknown. We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif-/- hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif-/- hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary occlusion and reperfusion in Mif-/- mice. Importantly, excess JNK activation also was observed after hypoxia-reoxygenation in human fibroblasts homozygous for the MIF allele with the lowest level of promoter activity. These data indicate that endogenous MIF inhibits JNK pathway activation during reperfusion and protects the heart from injury. These findings have clinical implications for patients with the low-expression MIF allele.
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PMID:Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. 1992 Mar 50