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首页> 外文期刊>The journals of gerontology.Series A. Biological sciences and medical sciences >Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction
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Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction

机译:衰老诱导的氧化应激导致内皮功能障碍

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Age is a risk factor for cardiovascular disease, suggesting a causal relationship between age-related changes and vascular damage. Endothelial dysfunction is an early pathophysiological hallmark in the development of cardiovascular disease. Senescence, the cellular equivalent of aging, was proposed to be involved in endothelial dysfunction, but functional data showing a causal relationship are missing. Endothelium-dependent vasodilation was measured in aortic rings ex vivo. We investigated aortas from aged C57Bl/6 mice (24-28 months), in which p16(INK4a) and p19(ARF) expression, markers of stress-induced senescence, were significantly induced compared to young controls (4-6 months). To reflect telomere shortening in human aging, we investigated aortas from telomerase deficient (Terc(-/-)) mice of generation 3 (G3). Endothelium-dependent vasodilation in aged wildtype and in Terc(-/-) G3 mice was impaired. A combination of the superoxide dismutase mimetic 1-Oxyl-2,2,6, 6-tetramethyl-4-hydroxypiperidine (TEMPOL) and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin significantly improved endothelium-dependent vasodilation in aged wildtype and Terc(-/-) G3 mice compared to untreated controls. We show that both, aging and senescence induced by telomere shortening, cause endothelial dysfunction that can be restored by antioxidants, indicating a role for oxidative stress. The observation that cellular senescence is a direct signalling event leading to endothelial dysfunction holds the potential to develop new targets for the prevention of cardiovascular disease.
机译:年龄是心血管疾病的危险因素,表明年龄相关的变化与血管损伤之间存在因果关系。内皮功能障碍是心血管疾病发展的早期病理生理标志。衰老与衰老的细胞等效,被认为与内皮功能障碍有关,但是缺少显示因果关系的功能数据。离体测量主动脉环中的内皮依赖性血管舒张。我们研究了来自老年C57Bl / 6小鼠(24-28个月)的主动脉,与年轻对照组(4-6个月)相比,其中p16(INK4a)和p19(ARF)表达(应激诱导衰老的标志物)被显着诱导。为了反映人类衰老中端粒的缩短,我们研究了第3代(G3)端粒酶缺陷(Terc(-/-))小鼠的主动脉。老年野生型和Terc(-/-)G3小鼠的内皮依赖性血管舒张功能受损。超氧化物歧化酶模拟物1-Oxyl-2,2,6,6-四甲基-4-羟基哌啶(TEMPOL)和烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶抑制剂Apocynin的结合显着改善了老年野生型和Terc的内皮依赖性血管舒张(-/-)G3小鼠与未处理的对照组相比。我们显示,端粒缩短引起的衰老和衰老均会引起内皮功能障碍,可通过抗氧化剂恢复,表明氧化应激的作用。细胞衰老是导致内皮功能障碍的直接信号转导事件,这一发现具有为预防心血管疾病开发新靶标的潜力。

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