Abstract
Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE−/− mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.
Highlights
Histone deacetylase 11 (HDAC11), the only class IV HDAC member, is reported to regulate immune activation [1], tumorigenesis [2], and cardiovascular diseases [3–5]
HDAC11 expression is upregulated and pyroptosis is activated in the aorta of high-fat diet (HFD)-fed ApoE−/− mice Our results showed that AS was successfully induced in ApoE−/− mice after HFD feeding for 8 weeks (Fig. 1A, B)
We found that HDAC11 protein and mRNA expressions were significantly increased in the aorta of ApoE−/− mice after HFD feeding for 8 weeks (Fig. 1E, F)
Summary
Histone deacetylase 11 (HDAC11), the only class IV HDAC member, is reported to regulate immune activation [1], tumorigenesis [2], and cardiovascular diseases [3–5]. HDAC11 may participate in the atherosclerosis (AS) process. HDAC11 deletion reduced tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β levels in serum and heart tissues of mice fed with fructose [3]. It has been reported that reconstitution of HDAC11 reduced IL-13 expression, while inhibition of HDAC11 increased IL-13 expression in CD4+ T cells of heart tissue in patients with myocarditis [7]. Another study found that inhibition of HDAC11 restored the IL-10 expression in B cells from allergic rhinitis patients [8]. These studies indicated that HDAC11 participated in the regulation of inflammation. Whether HDAC11 participates in the regulation of pyroptosis in AS process remains unknown
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