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Published on: May 31, 2016
Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis
Peng Li1,2, Ying Wang2, Xue Liu2
1Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China.
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.
Insights
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition reduces diabetic atherosclerotic calcification and vessel stiffening by suppressing Runx2. This pathway involves Stat1-mediated vascular smooth muscle cell and macrophage changes, offering a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Molecular Medicine
Background:
- Accelerated atherosclerotic calcification and plaque burden are significant complications in diabetes.
- The precise regulatory mechanisms of atherosclerotic calcification in diabetic conditions remain incompletely understood.
Purpose of the Study:
- To investigate the role of Poly(ADP-ribose) polymerase-1 (PARP-1) in diabetic atherosclerotic calcification.
- To elucidate the molecular pathways, including Stat1 and Runx2, involved in this process.
Main Methods:
- Utilized mouse models to study the effects of PARP-1 deletion on diabetic atherosclerotic calcification and vascular stiffening.
- Examined the regulation of vascular smooth muscle cell phenotype switching and macrophage polarization.
- Investigated the interaction between Stat1, Runx2, and atherosclerotic calcification in vitro and in vivo.
Main Results:
- PARP-1 deficiency significantly attenuated diabetic atherosclerotic calcification and decreased vessel stiffening in mice.
- PARP-1 deficiency regulated Stat1-mediated synthetic phenotype switching in vascular smooth muscle cells and macrophage polarization.
- Stat1 was identified as a positive transcription factor that directly binds to the Runx2 promoter, promoting atherosclerotic calcification in diabetes.
Conclusions:
- PARP-1 plays a critical role in facilitating diabetic atherosclerotic calcification through Stat1-mediated activation of Runx2 expression.
- Inhibition of PARP-1 may offer a novel therapeutic strategy for managing atherosclerotic calcification in diabetic patients.
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