Maeda Morihiko, Hayashi Toshio, Mizuno Natsumi, Hattori Yuichi, Kuzuya Masafumi
Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
PLoS One. 2015 Apr 16;10(4):e0123169. doi: 10.1371/journal.pone.0123169. eCollection 2015.
Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated the effect of fluctuating glucose levels on human endothelial senescence. Constant high glucose increased senescence-associated-β-galactosidase (SA-β-gal) activity, a widely used marker for cellular senescence. Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage. However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown. However, constant high glucose activated telomerase and shortened telomere length, which suggested replicative senescence. Intermittent but not constant high glucose strikingly up-regulated the expression of p22phox, an NADPH oxidase component, increasing superoxide. The small interfering RNA of p22phox undermined the increase in SA-β-gal activity induced by intermittent high glucose. Conclusively, intermittent high glucose can promote vascular endothelial senescence more than constant high glucose, which is in partially dependent on superoxide overproduction.
糖耐量受损以餐后高血糖为特征，常见于老年人，是糖尿病的一个重要前期阶段，也是动脉粥样硬化发生发展的独立危险因素。据报道，内皮细胞衰老先于动脉粥样硬化。我们曾报道，持续高糖刺激比高血压或血脂异常刺激更显著地导致内皮细胞衰老。在本研究中，我们评估了血糖波动对人内皮细胞衰老的影响。持续高糖增加了衰老相关β半乳糖苷酶（SA-β-gal）活性，这是一种广泛用于细胞衰老的标志物。有趣的是，在间歇性高糖情况下，这种作用更明显，同时p21和p16INK4a（与DNA损伤相关的衰老相关蛋白）也增加。然而，端粒酶未被激活，端粒长度未缩短，表明是应激诱导的衰老。而持续高糖激活了端粒酶并缩短了端粒长度，提示是复制性衰老。间歇性而非持续性高糖显著上调了NADPH氧化酶成分p22phox的表达，增加了超氧化物的产生。p22phox的小干扰RNA削弱了间歇性高糖诱导的SA-β-gal活性增加。总之，间歇性高糖比持续性高糖更能促进血管内皮细胞衰老，这部分依赖于超氧化物的过度产生。
