Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release
Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release
复制标题
磷酸盐诱导的自噬通过减少基质囊泡释放来抵消血管钙化。
DOI：
10.1038/ki.2012.482
复制
发表时间：
2013-06-01
影响因子：
19.6
通讯作者：
Wang, Xian
中科院分区：
文献类型：
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作者：
Dai, Xiao-Yan;Zhao, Ming-Ming;Wang, Xian
自噬是一个动态的和高度调节的自我消化过程，负责细胞存活和对氧化应激的反应。由于氧化应激在尿毒症中增加并与血管钙化相关，我们研究了自噬在磷酸盐诱导的血管钙化中的作用。在体外磷酸盐诱导的血管平滑肌细胞（VSMCs）钙化模型和慢性肾功能衰竭动物模型中，超氧化物歧化酶模拟MnTMPyP，超氧化物歧化酶-2过表达和钠依赖性磷酸盐协同转运蛋白Pit 1的敲除抑制了自噬。虽然磷酸盐诱导的VSMC凋亡减少了自噬抑制剂（3-甲基腺嘌呤）和自噬蛋白5的敲低，钙沉积在VSMC中的自噬抑制过程中增加，甚至与凋亡抑制剂Z-VAD-FMK。自噬诱导剂丙戊酸可减少钙化。此外，3-甲基腺嘌呤显着促进磷酸盐诱导的基质囊泡释放碱性磷酸酶活性增加。因此，自噬可能是一种内源性保护机制，通过减少基质囊泡的释放来抵消磷酸盐诱导的血管钙化。影响自噬反应的治疗剂可能有利于治疗衰老或疾病相关的血管钙化和骨质疏松症。
Autophagy is a dynamic and highly regulated process of self-digestion responsible for cell survival and reaction to oxidative stress. As oxidative stress is increased in uremia and is associated with vascular calcification, we studied the role of autophagy in vascular calcification induced by phosphate. In anin vitrophosphate-induced calcification model of vascular smooth muscle cells (VSMCs) and in anin vivomodel of chronic renal failure, autophagy was inhibited by the superoxide dismutase mimic MnTMPyP, superoxide dismutase-2 overexpression, and by knockdown of the sodium-dependent phosphate cotransporter Pit1. Although phosphate-induced VSMC apoptosis was reduced by an inhibitor of autophagy (3-methyladenine) and knockdown of autophagy protein 5, calcium deposition in VSMCs was increased during inhibition of autophagy, even with the apoptosis inhibitor Z-VAD-FMK. An inducer of autophagy, valproic acid, decreased calcification. Furthermore, 3-methyladenine significantly promoted phosphate-induced matrix vesicle release with increased alkaline phosphatase activity. Thus, autophagy may be an endogenous protective mechanism counteracting phosphate-induced vascular calcification by reducing matrix vesicle release. Therapeutic agents influencing the autophagic response may be of benefit to treat aging or disease-related vascular calcification and osteoporosis.