Abstract
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.
Highlights
Vascular calcification is prevalent in patients suffering from diabetes and has been strongly associated with adverse cardiovascular outcome[1,2]
We demonstrate for the first time that Poly [ADP-ribose] polymerase 1 (PARP-1) plays a novel role in the regulation of osteogenic differentiation in both vascular smooth muscle cells (VSMCs) and macrophages regardless of the high glucose (HG) milieu
Our results suggest that PARP-1 regulates hyperglycemia-accelerated arteriosclerotic calcification by targeting Stat1/Runx[2] axis
Summary
Vascular calcification is prevalent in patients suffering from diabetes and has been strongly associated with adverse cardiovascular outcome[1,2]. Arteriosclerotic calcification, which represents a significant predictor of susceptibility to plaque rupture, is directly driven by the osteogenic differentiation of VSMCs and the. Runx[2] binds to the osteoblast-specific cis-acting element 2, which is found in the promoter regions of both osteocalcin and alkaline phosphatase[9], and regulates their expression. This may explain the requirement for Runx[2] as a molecular switch for osteogenic differentiation and the inability of any parallel pathway to overcome its absence.
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