Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis
Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis
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PARP-1 的缺失通过 Stat1/Runx2 轴减轻糖尿病动脉硬化钙化
DOI：
10.1038/s41419-019-2215-8
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发表时间：
2020-01-10
影响因子：
9
通讯作者：
Zhang, Ming-xiang
中科院分区：
文献类型：
--
作者：
Li, Peng;Wang, Ying;Zhang, Ming-xiang
加速的动脉粥样硬化钙化是斑块负担的原因，尤其是在糖尿病中。糖尿病患者动脉粥样硬化钙化的调节机制尚不清楚。在这里，我们表明，删除PARP-1，在不同的代谢并发症的主要酶，减弱糖尿病动脉粥样硬化钙化和减少血管硬化小鼠通过Runx 2抑制。具体而言，PARP-1缺乏通过调节Stat 1介导的血管平滑肌细胞合成表型转换和巨噬细胞极化来减少糖尿病动脉钙化。同时，血管平滑肌细胞和巨噬细胞在成骨培养基中表现出成骨分化，这被PARP-1/Stat 1抑制减弱。值得注意的是，Stat 1通过直接结合Runx 2的启动子并促进糖尿病中的动脉粥样硬化钙化而作为正性转录因子。我们的研究结果确定了PARP-1的一个新功能，其中代谢紊乱相关刺激激活由Stat 1转录介导的Runx 2表达，以促进糖尿病动脉钙化。因此，PARP-1抑制可能是治疗这种具有挑战性的并发症的有效疗法。
Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.