Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs

Abstract

Background Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis. Methods To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1β, both of which are the primary methods for assessing pyroptosis. Results IL-18 and IL-1β concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1β and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs. Conclusions Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.

Accelerating Cellular Uptake with Unnatural Amino Acid for Inhibiting Immunosuppressive Cancer Cells

“…These inhibitors only marginally rescued SJSA1 cells, even at high concentrations. Disulfiram, known to block gasdermin D pore formation and inflammasome‐mediated pyroptosis, [25] along with ferrostatin (a ferroptosis inhibitor [26] ), SP600125 (a lysosome permeation inhibitor), all showed minimal rescue effects. Deferoxamine mesylate (DFO), another ferroptosis inhibitor, [26] and N−acetyl−L‐cysteine (NAC), an ROS scavenger, [27] exhibited some dosage dependent rescue effect, but these effects were modest.…”

Inflammation and immunity in the pathogenesis of hypoxic pulmonary hypertension

“…IL-1b and IL-18 (101) have been shown to regulate the recruitment of pulmonary perivascular macrophages, resist hypoxia-induced pyroptosis (102), and synergistically activate the caspase-1/STAT3 pathway, promoting macrophage-based inflammatory cell infiltration (103). Furthermore, serum levels of IL-1b and IL-18 (104) are reliable predictors of pulmonary vascular remodeling and HPH risk.…”

Epigenetic regulation of programmed cell death in hypoxia-induced pulmonary arterial hypertension

“…Studies from Hu et al. demonstrated disulfiram (DSF) attenuated vascular remodeling and hypoxia-induced PAH by inhibiting GSDMD cleavage and pyroptosis in human pulmonary artery smooth muscle cells (hPASMCs) ( 42 ). Additionally, Zhang et al.…”