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

Abstract

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.

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

“…Autophagic flux was upregulated in VCN in both a chronic in vivo renal failure rat model, as well as in an in vitro Pi-induced VSMC calcification assay [ 51 ]. This observation was also confirmed in other studies, where autophagy was upregulated in in vitro and in vivo models of VCN [ 52 , 53 ]. Conversely, there is also evidence that mTOR (an inhibitor of autophagy) is upregulated in VSMC calcification [ 54 ].…”

“…Dai et al (2013a) showed that inhibiting autophagy with 3-MA or Atg5 knockdown enhances VCN in vitro. Other studies confirmed that 3-MA aggravates VSMC calcification [52,53,72]. Furthermore, multiple studies added 3-MA, in combination with an autophagy, inducing pharmacological intervention, thereby showing that 3-MA abolishes the beneficial effects of autophagy induction on VCN [59,61,64,66,67].…”

“…In line with these findings, epigenetic regulation of mTOR activity was also altered in VCN. Histone deacetylase 1 (HDAC1) was downregulated in VCN while lysine-specific histone demethylase A1 (LSD1) was upregulated, resulting in enhanced mTOR activity [ 52 ]. Lastly, hydroxyapatite was shown to cause cell injury, leading to decreased lysosomal integrity and facilitating VCN [ 55 ].…”

“…Lastly, HDAC1 was downregulated in VCN, while LSD1 was upregulated. HDAC1 overexpression or LSD1 silencing resulted in less VCN, mTOR inhibition and autophagy induction [ 52 ].…”

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…DD406/7 are identified as key residues for GTPase-activating protein (GAP) activity toward recombination activating genes (RAGs) (GATOR) 2 binding so that Sestrin2 can inhibit mTORC1 association with lysosome for its activation Ho et al, 2016). LSD1, upon deacetylation by histone deacetylase 1 (HDAC1), reduced the methylations of H3K4me2 in the promoter region of Sesn2, thereby suppressed the gene expression of Sesn2 in chronic renal failure (CRF) (Zhou et al, 2020). Jumonji domain-containing protein D3 (JMJD3), a histone demethylase, inhibited the transcription of Sesn2 by reducing the methylations of H3K27me3 in the promoter region of Sesn2 in cardiomyopathy (Wang P. et al, 2020).…”