Epigenetic repression of RGS2 transcription by HDAC5 contributes to deep vein thrombosis.

AIMS: Endothelial injury caused by excessive inflammatory response is a primary factor leading to the occurrence and development of deep vein thrombosis (DVT). HDAC5, a class IIa histone deacetylase, is associated with inflammatory response. However, the effect of HDAC5 on endothelial cell inflammatory damage and thrombosis and the underlying mechanism remain elusive. This research aimed to investigate the epigenetic regulation of HDAC5 during endothelial cell inflammatory response and thrombosis progression. MATERIALS AND METHODS: Quantitative real-time PCR, western blot and functional tests were employed to reveal the regulatory effect of HDAC5 intervention on endothelial cell damage resulted from inflammation in DVT. H&E and immunohistochemical staining were applied to the mouse model to validate HDAC5-RGS2 pathway for prevention and treatment of deep vein thrombosis. KEY FINDINGS: We found that HDAC5 deletion ameliorated endothelial dysfunction and DVT progression. Mechanically, mRNA sequence analysis indicated that HDAC5 regulated the course of inflammation-related endothelial cell damage by affecting transcription of the downstream target gene RGS2. Functional knockdown experiments confirmed HDAC5-dependent transcriptional repression of RGS2 and downstream PI3K-Akt signal pathway activation, which was associated with augmented endothelial injury. Finally, HDAC5 inhibitors (LMK235) and AAV2/8-oeRGS2 treatment mitigated endothelial cell inflammatory response in vitro and ameliorated DVT progression in vivo, respectively. SIGNIFICANCE: Our research demonstrated that endothelial cell specific HDAC5 inhibition ameliorates inflammatory response and DVT progression via damping RGS2-PI3K/Akt signaling, and a potential HDAC5 targeting strategy for treating deep vein thrombosis.