Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceramide has been shown to be a key signaling molecule involved in the apoptotic effect of tumor necrosis factor alpha (TNF-alpha) and other cytokines. Given the importance of cytokines such as TNF-alpha in myocardial ischemia-reperfusion injury, we hypothesize that ceramide is increased during ischemia or reperfusion, and that the activity of enzymes responsible for its production or breakdown should be increased and/or decreased, respectively. Therefore, in the present study, we characterized the enzymatic activities responsible for ceramide production and metabolism in the myocardium of rats, and determined the contribution of these enzymes to altered ceramide levels during myocardial ischemia and reperfusion. The basal ceramide concentration in the myocardium of rats was 34.0 pmol/mg tissue. As determined by the conversion of 14C-sphingomyelin into ceramide and 14C-choline phosphate, both neutral (N-) and acidic (A-) SMase were detected in the myocardium, with a conversion rate of 0.09 +/- 0.008 and 0.32 +/- 0.05 nmol/min per mg protein, respectively. The activity of A-SMase (78 % of total cellular activity) was significantly higher in microsomes than in cytosol, while the activity of N-SMase was similar in both fractions. Ceramidase, a ceramide-metabolizing enzyme, was also detected in the myocardium of rats. It metabolized ceramide into sphingosine at a rate of 9.94 +/- 0.42 pmol/min per mg protein. In anesthetized rats, 30 min of ischemia had no apparent effect on ceramide concentrations in the myocardium, while 30 min of ischemia followed by 3 h of reperfusion resulted in a significant increase in ceramide by 48 %. The activities of both N- and A-SMase were reduced by 44 % and 32 %, respectively, in the myocardium subjected to ischemia followed by reperfusion, but unaltered in the ischemic myocardium. It was also found that myocardial ischemia followed by reperfusion produced a marked inhibition of ceramidase (by 29 %). These results demonstrate that the myocardium of rats expresses N- and A-SMase and ceramidase, which contribute to the production and metabolism of ceramide, respectively. Tissue ceramide concentrations increased in reperfused myocardium. These increases in ceramide were not associated with enhanced SMase activity, but rather with reduced ceramidase activity.
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PMID:Production and metabolism of ceramide in normal and ischemic-reperfused myocardium of rats. 1140 20

The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in BimL phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance.
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PMID:Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. 1694 86

Ceramide, a bioactive membrane sphingolipid, functions as an important second messenger in apoptosis and cell signaling. In response to stresses, it may be generated by de novo synthesis, sphingomyelin hydrolysis, and/or recycling of complex sphingolipids. It is cleared from cells through the activity of ceramidases, phosphorylation to ceramide-1-phosphate, or resynthesis into more complex sphingolipids. Ischemia/reperfusion (IR) injury occurs when oxygen/nutrition is rapidly reintroduced into ischemic tissue, resulting in cell death and tissue damage, and is a major concern in diverse clinical settings, including organ resection and transplantation. Numerous reports show that ceramide levels are markedly elevated during IR. Mitochondria are major sites of reactive oxygen species (ROS) production and play a key role in IR-induced and ceramide-mediated cell death and tissue damage. During the development of IR injury, the initial response of ROS and TNF-alpha production activates two major ceramide generating pathways (sphingomyelin hydrolysis and de novo ceramide synthesis). The increased ceramide has broad effects depending on the IR phases, including both pro- and antiapoptotic effects. Therefore, strategies that reduce the levels of ceramide, for example, by modulation of ceramidase and/or sphingomyelinases activities, may represent novel and promising therapeutic approaches to prevent or treat IR injury in diverse clinical settings.
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PMID:Ceramide and Ischemia/Reperfusion Injury. 2961 Jun 85