HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

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.

A newly identified pyroptosis-related gene signature for predicting prognosis of patients with hepatocellular cancer

“…GSDME / DFNA5 (deafness, autosomal dominant 5) is a gasdermin superfamily gene correlated with autosomal dominant nonsyndromic hearing impairment ( 22 ). GSDME was recently discovered as a pore-forming protein that is triggered by caspase-3 cleavage, leading to secondary necrosis upon cell apoptosis or initial necrosis without the need for an apoptotic stage, dubbed pyroptosis-like necrosis ( 23 ). GSDME has been shown to operate as a potential tumor suppressor gene in a significant proportion of gastric, colorectal, and breast cancers ( 24 , 25 ).…”

Uric Acid Induces a Proatherothrombotic Phenotype in Human Endothelial Cells by Imbalancing the Tissue Factor/Tissue Factor Pathway Inhibitor Pathway

“…Again, in another set of experiments, GSDMD expression, as an effector of pyroptosis, was also evaluated at 12 hour time point in line with other reports. 25…”

“…Caspase-1 levels were measured at 8 hours by western blot using Caspase-1 p20 antibody (Biorbyt orb221355). Cleaved Gasdermin (GSDMD-N) expression was detected at 12 hours using a specific antibody (Cell Signaling Technology, #36425) as already reported (25). After detecting Caspase-1 and GSDMD-N, the membranes were stripped and then treated to detect tubulin expression as housekeeping protein.…”

“…Again, in another set of experiments, GSDMD expression, as an effector of pyroptosis, was also evaluated at 12 hour time point in line with other reports. 25 Since UA exerts its effects by binding to a specific receptor, the urate transporter 1 (URAT1) localized in several types of cells including vascular endothelial cells, 26 in another set of experiments, effects of URAT1 inhibition by probenecid (Sigma Aldrich, Milan, Italy) were evaluated by preincubating HUVEC with this drug (1 mM) 30 minutes before cell stimulation with UA (9 mg/dL), as already reported. 27 Effects of Uric Acid on TF-mRNA Levels TF gene levels were evaluated in stimulated HUVECs as previously described.…”

Artificial Intelligence-Assisted Bioinformatics, Microneedle, and Diabetic Wound Healing: A “New Deal” of an Old Drug

“…The HADC family plays a significant role in diabetic wounds or inflammation regulation, 20 e.g., HDAC6 regulates IL-1β secretion and IL-10 expression in diabetic wounds' macrophages, 21 targeting HDAC6 weakens macrophage pyroptosis via the NF-κB/ NLRP3 pathway, 22 and HDAC3 negatively regulates the M2 macrophage phenotype. 23 Moreover, a recent study finds that HDAC11 can aggravate the endothelial cell pyroptosis through NLRP3 inflammasome, 24 which provides reference and enlightenment for diabetic wounds related to cell pyroptosis and angiogenesis. However, it is still unknown if HDAC4 could play a role in diabetic wounds (Figure 1a).…”