HDAC1-mediated deacetylation of LSD1 regulates vascular calcification by promoting autophagy in chronic renal failure.

Chronic renal failure (CRF) is commonly associated with various adverse consequences including pathological vascular calcification (VC), which represents a significant clinical concern. Existing literature has suggested the involvement of histone deacetylases (HDACs) in the progression of CRF-induced VC. However, the underlying molecular mechanisms associated with HDACs remain largely unknown. Therefore, we established the adenine-induced CRF rat model and in vitro VC models based on vascular smooth muscle cells (VSMCs) to examine HDAC1/lysine demethylase 1A (LSD1)/SESN2 as a novel molecular pathway in CRF-induced VC. Our initial results demonstrated that HDAC1 reduced the formation of VC in vivo and in vitro. HDAC1 was found to deacetylate LSD1, which subsequently led to impaired transcriptional activity in CRF-induced VC. Moreover, our results illustrated that LSD1 diminished the enrichment of H3K4me2 at the SESN2 promoter. Autophagy was identified as a vasculo-protective element against calcification in VC. Finally, we found that the inhibitory effects of HDAC1 overexpression on VC were partially abolished via over-expressed LSD1 in adenine-induced CRF model rats and in high phosphate-induced VSMCs. Taken together, these results highlight the crucial role of HDAC1 as an antagonistic factor in the progression of VC in CRF, and also revealed a novel regulatory mechanism by which HDAC1 operates. These findings provide significant insight and a fresh perspective into promising novel treatment strategies by up-regulating HDAC1 in CRF.