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Histone demethylase KDM3a, a novel regulator of vascular smooth muscle cells, controls vascular neointimal hyperplasia in diabetic rats

      Highlights

      • Histone demethylase KDM3a, a novel regulator of vascular smooth muscle cells, controls vascular neointimal hyperplasia in diabetic rats.
      • KDM3a and H3M9me2 were involved in metabolic memory after vascular injury in diabetic condition.
      • KDM3a expression is closely associated with the development of neointimal hyperplasia in diabetes.
      • KDM3a might function as a key regulator of vascular remodeling in diabetes via Rho/ROCK and AngII/AGTR1 signaling pathways.

      Abstract

      Background and aims

      Deregulation of histone demethylase KDM3a, an important regulator for H3K9 methylation, is correlated with obesity and abnormal metabolism in rodent models. However, the function of KDM3a in vascular remodeling under diabetic condition is unknown.

      Methods

      Adenoviruses expressing KDM3a and lentiviruses expressing KDM3a-targeting siRNA were generated to study the role of KDM3a both in vivo and in vitro. The carotid artery balloon injury model was established in diabetic SD rats to evaluate the significance of KDM3a in vascular injury.

      Results

      Diabetic vessels were associated with sustained loss of histone H3 lysine 9 di-methylation (H3K9me2) and elevation of KDM3a. This phenomenon was induced by high glucose (HG) and was persistently present even after removal from diabetic condition and high glucose in vascular smooth muscle cells (VSMCs). After 28-day balloon injury, KDM3a overexpression accelerated while KDM3a knockdown reduced neointima formation, following vascular injury in diabetic rats without glucose control. Microarray analysis revealed KDM3a altered the expression of vascular remodeling genes; particularly, it mediated the Rho/ROCK and AngII/AGTR1 pathways. In the in vivo study, HG and Ang II-stimulated proliferation and migration of VSMCs were enhanced by KDM3a overexpression, whereas markedly prevented by KDM3a knockdown. KDM3a regulated the transcription of AGTR1 and ROCK2 via controlling H3K9me2 in the proximal promoter regions.

      Conclusions

      Histone demethylase KDM3a promotes vascular neointimal hyperplasia in diabetic rats via AGTR1 and ROCK2 signaling pathways. Targeting KDM3a might represent a promising therapeutic approach for the prevention of coronary artery disease with diabetes.

      Keywords

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