Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis was tested that endothelin-1 (ET-1)-induced superoxide (O(2)(-)) generation mediates post-ischemic coronary endothelial injury, that ischemic preconditioning (IPC) affords endothelial protection by preventing post-ischemic ET-1, and thus O(2)(-), generation, and that opening of the mitochondrial ATP-dependent potassium channel (mK(ATP)) triggers the mechanism of IPC. Furthermore, the study was aimed at identifying the source of O(2)(-) mediating the endothelial injury. Langendorff-perfused guinea-pig hearts were subjected either to 30 min ischemia/35 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min washout of mK(ATP) opener diazoxide (0.5 mM). Coronary flow responses to acetylcholine (ACh) served as a measure of endothelium-dependent vascular function. Myocardial outflow of ET-1 and O(2)(-) and functional recoveries were followed during reperfusion. NADPH oxidase and xanthine oxidase (XO) activities were measured in cardiac homogenates. IR augmented ET-1 and O(2)(-) outflow and impaired ACh response. All these effects were attenuated or prevented by IPC and diazoxide, and 5-hydroxydecanoate (a selective mK(ATP) blocker) abolished the effects of IPC and diazoxide. Superoxide dismutase and tezosentan (a mixed ET-1-receptor antagonist) mimicked the effects of IPC, although they had no effect on the ET-1 generation. IR augmented also the activity of NADPH oxidase and XO. Apocynin treatment, that resulted in NADPH oxidase inhibition, prevented XO activation and O(2)(-) generation in IR hearts. The inhibition of XO, either by allopurinol or feeding the animals with tungsten-enriched chow, prevented post-ischemic O(2)(-) generation, although these interventions had no effect on the NADPH activity. In addition, the post-ischemic activation of NADPH oxidase and XO, and O(2)(-) generation were prevented by IPC, tezosentan, thenoyltrifluoroacetone (mitochondrial complex II inhibitor), and tempol (cell-membrane permeable O(2)(-) scavenger). In guinea-pig heart: (i) ET-1-induced O(2)(-) generation mediates post-ischemic endothelial dysfunction; (ii) IPC and diazoxide afford endothelial protection by attenuating the ET-1, and thus O(2)(-) generation, and the mK(ATP) opening triggers the protection; (iii) the NADPH oxidase maintains the activity of XO, and the XO-derived O(2)(-) mediates the endothelial injury, and (iv) ET-1 and O(2)(-) (probably of mitochondrial origin) are upstream activators of the NADPH oxidase-XO cascade, and IPC prevents the cascade activation and the endothelial dysfunction by preventing the ET-1 generation.
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PMID:Preconditioning protects endothelium by preventing ET-1-induced activation of NADPH oxidase and xanthine oxidase in post-ischemic heart. 1715 94

We hypothesized that, due to a cross-talk between cytoplasmic O2--sources and intraluminally expressed xanthine oxidase (XO), intraluminal O2- is instrumental in mediating intraluminal (endothelial dysfunction) and cytosolic (p38 and ERK1/2 MAPKs phosphorylation) manifestations of vascular oxidative stress induced by endothelin-1 (ET-1) and angiotensin II (AT-II). Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2-. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2-, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II+tezosentan) triggered intraluminal O2-, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox) and XO activation. These effects were: (i) prevented by blocking PKC (chelerythrine), Nox (apocynin), mitochondrial ATP-dependent K+ channel (5-HD), complex II (TTFA), and XO (allopurinol); (ii) mimicked by the activation of Nox (NADH); and mitochondria (diazoxide, 3-NPA) and (iii) the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2- (SOD) and XO, and were mimicked by XO activation (hypoxanthine). Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2-.
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PMID:Obligatory role of intraluminal O2- in acute endothelin-1 and angiotensin II signaling to mediate endothelial dysfunction and MAPK activation in guinea-pig hearts. 2535 Jan 9