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12-lipoxygenase in porcine coronary microcirculation: implications for coronary vasoregulation.

机译:猪冠状动脉微循环中的12-脂氧合酶:对冠脉血管调节的影响。

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摘要

Noncyclooxygenase metabolites of arachidonic acid (AA) have been proposed to mediate endothelium-dependent vasodilation in the coronary microcirculation. Therefore, we examined the formation and bioactivity of AA metabolites in porcine coronary (PC) microvascular endothelial cells and microvessels, respectively. The major noncyclooxygenase metabolite produced by microvascular endothelial cells was 12(S)-hydroxyeicosatetraenoic acid (HETE), a lipoxygenase product. 12(S)-HETE release was markedly increased by pretreatment with 13(S)-hydroperoxyoctadecadienoic acid but not by the reduced congener 13(S)-hydroxyoctadecadienoic acid, suggesting oxidative upregulation of 12(S)-HETE output. 12(S)-HETE produced potent relaxation and hyperpolarization of PC microvessels (EC(50), expressed as -log[M] = 13.5 +/- 0.5). Moreover, 12(S)-HETE potently activated large-conductance Ca(2+)-activated K(+) currents in PC microvascular smooth muscle cells. In contrast, 12(S)-HETE was not a major product of conduit PC endothelial AA metabolism and did not exhibit potent bioactivity in conduit PC arteries. We suggest that, in the coronary microcirculation, 12(S)-HETE can function as a potent hyperpolarizing vasodilator that may contribute to endothelium-dependent relaxation, particularly in the setting of oxidative stress.
机译:花生四烯酸(AA)的非环加氧酶代谢物已被提议在冠状动脉微循环中介导内皮依赖性血管舒张。因此,我们分别检查了猪冠状动脉(PC)微血管内皮细胞和微血管中AA代谢物的形成和生物活性。微血管内皮细胞产生的主要非环加氧酶代谢产物是脂氧合酶产物12(S)-羟基二十碳四烯酸(HETE)。 12(S)-HETE的释放通过用13(S)-氢过氧十八碳二烯酸进行预处理而显着增加,但还原的13(S)-羟基十八碳二烯酸未降低,这表明12(S)-HETE输出的氧化上调。 12(S)-HETE产生了PC微血管的强力松弛和超极化作用(EC(50),表示为-log [M] = 13.5 +/- 0.5)。此外,PC微血管平滑肌细胞中的12(S)-HETE有效激活大电导Ca(2+)激活的K(+)电流。相反,12(S)-HETE不是导管PC内皮AA代谢的主要产物,并且在导管PC动脉中没有表现出有效的生物活性。我们建议,在冠状动脉微循环中,12(S)-HETE可以作为有效的超极化血管舒张药,可能有助于内皮依赖性舒张,特别是在氧化应激的情况下。

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