Nilsson Jenny, Nilsson Lisa M, Chen Yung-Wu, Molkentin Jeffery D, Erlinge David, Gomez Maria F
Department of Experimental Medical Science, Lund University, Sweden.
Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):794-800. doi: 10.1161/01.ATV.0000209513.00765.13. Epub 2006 Feb 9.
Hyperglycemia has been suggested to play a role in the development of vascular disease associated with diabetes. Atypical Ca2+ signaling and gene expression are characteristic of vascular dysfunction; however, little is known regarding the effects of high glucose on Ca2+-dependent transcription in the vascular wall.
Using confocal immunofluorescence, we show that modest elevation of extracellular glucose (ie, from 2 to 11.5 mmol/L) increased [Ca2+]i, leading to nuclear accumulation of nuclear factor of activated T cells (NFAT) in intact cerebral arteries from mouse. This was accompanied by increased NFAT-dependent transcriptional activity. Both the increase in Ca2+ and NFAT activation were prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. We provide evidence that the potent vasoconstrictors and growth stimulators UTP and UDP mediate glucose-induced NFAT activation via P2Y receptors. NFAT nuclear accumulation was inhibited by the voltage-dependent Ca2+ channel blockers verapamil and nifedipine, the calcineurin inhibitor cyclosporine A, and the novel NFAT blocker A-285222. High glucose also regulated glycogen synthase kinase 3beta and c-Jun N-terminal kinase activity, yielding decreased kinase activity and reduced export of NFAT from the nucleus, providing additional mechanisms underlying the glucose-induced NFAT activation.
Our results identify the calcineurin/NFAT signaling pathway as a potential metabolic sensor for the arterial smooth muscle response to high glucose.
高血糖被认为在糖尿病相关血管疾病的发展中起作用。非典型的Ca2+信号传导和基因表达是血管功能障碍的特征；然而，关于高糖对血管壁中Ca2+依赖性转录的影响知之甚少。
使用共聚焦免疫荧光技术，我们发现细胞外葡萄糖适度升高（即从2 mmol/L升高到11.5 mmol/L）会增加细胞内Ca2+浓度（[Ca2+]i），导致小鼠完整脑动脉中活化T细胞核因子（NFAT）的核内积累。这伴随着NFAT依赖性转录活性的增加。外切核苷酸酶Apyrase可阻止Ca2+的增加和NFAT的激活，提示这一机制涉及细胞外核苷酸的释放。我们提供证据表明，强效血管收缩剂和生长刺激剂UTP和UDP通过P2Y受体介导葡萄糖诱导的NFAT激活。电压依赖性Ca2+通道阻滞剂维拉帕米和硝苯地平、钙调神经磷酸酶抑制剂环孢素A以及新型NFAT阻滞剂A-285222可抑制NFAT的核内积累。高糖还调节糖原合酶激酶3β和c-Jun氨基末端激酶的活性，导致激酶活性降低以及NFAT从细胞核的输出减少，这为葡萄糖诱导的NFAT激活提供了额外的机制。
我们的结果表明钙调神经磷酸酶/NFAT信号通路是动脉平滑肌对高糖反应的潜在代谢传感器。
