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首页> 外文期刊>Cell and Tissue Research >High-glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPAR alpha and PPAR beta/delta
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High-glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPAR alpha and PPAR beta/delta

机译：高糖增加人血管平滑肌细胞中NADPH氧化酶的表达和激活是由4-羟基壬烯激活的PPARα和PPARβ/δ介导的

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摘要

High glucose induces vascular smooth muscle cell (SMC) dysfunction by generating oxidative stress attributable, in part, to the up-regulated NADPH oxidases (Nox). We have attempted to elucidate the high-glucose-generated molecular signals that mediate this effect and hypothesize that products of high-glucose-induced lipid peroxidation regulate Nox by activating peroxisome proliferator-activated receptors (PPARs). Human aortic SMCs were exposed to glucose (5.5-25 mM) or 4-hydroxynonenal (1-25 mu M, 4-HNE). Lucigenin assay, real-time polymerase chain reaction, western blot, and promoter analyses were employed to investigate Nox. We found that high glucose generated an increase in Nox activity and expression. It also promoted oxidative stress that consequently induced lipid peroxidation, which resulted in the production of 4-HNE. Pharmacological inhibition of Nox activity significantly reduced the formation of high-glucose-induced 4-HNE. Exposure of SMCs to noncytotoxic concentrations (1-10 mu M) of 4-HNE alone mimicked the effect of high glucose incubation, whereas scavenging of 4-HNE by N-acetyl L-cysteine completely abolished both the effects of high glucose and 4-HNE. The latter exerted its effect by activating PPAR alpha and PPAR beta/delta, but not PPAR gamma, as assessed pharmacologically by the inhibitory effect of selective antagonists and following the silencing of the expression of these receptors. These new data indicate that 4-HNE, generated following Nox activation, functions as an endogenous activator of PPAR alpha and PPAR beta/delta. The newly discovered "lipid peroxidation products-PPARs-Nox axis" represents a novel mechanism of Nox regulation and an additional therapeutic target for oxidative stress in diabetes.
机译：高葡萄糖可通过产生部分归因于NADPH氧化酶（Nox）上调的氧化应激来诱导血管平滑肌细胞（SMC）功能障碍。我们已尝试阐明介导此作用的高糖生成的分子信号，并假设高糖诱导的脂质过氧化产物通过激活过氧化物酶体增殖物激活受体（PPAR）来调节Nox。将人主动脉SMC暴露于葡萄糖（5.5-25 mM）或4-羟基壬烯醛（1-25μM，4-HNE）。荧光素测定，实时聚合酶链反应，免疫印迹和启动子分析被用来研究Nox。我们发现高葡萄糖会导致Nox活性和表达增加。它还促进了氧化应激，从而导致脂质过氧化，从而导致了4-HNE的产生。 Nox活性的药理抑制作用显着降低了高糖诱导的4-HNE的形成。仅将SMCs暴露于4-HNE的非细胞毒性浓度（1-10μM）可模仿高葡萄糖温育的效果，而通过N-乙酰基L-半胱氨酸清除4-HNE则完全消除了高葡萄糖和4-HNE的影响。 HNE。后者通过激活PPARα和PPARβ/δ而不是PPARγ发挥作用，如通过选择性拮抗剂的抑制作用并在这些受体的表达沉默后进行药理评估。这些新数据表明，在Nox激活后生成的4-HNE充当PPAR alpha和PPAR beta / delta的内源性激活剂。新发现的“脂质过氧化产物-PPARs-Nox轴”代表了NOx调节的新机制以及糖尿病氧化应激的另一治疗靶标。

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