Novel Role for Tranilast in Regulating NLRP3 Ubiquitination, Vascular Inflammation, and Atherosclerosis

Abstract

Background Aberrant activation of the NLRP 3 (nucleotide‐binding oligomerization domain, leucine‐rich repeat–containing receptor family pyrin domain‐containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP 3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP 3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP 3 ubiquitination blunts the assembly and activation of the NLRP 3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low‐density lipoprotein receptor– or apolipoprotein E–deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP 3 ubiquitination. We showed that tranilast restricted NLRP 3 oligomerization and inhibited NLRP 3 inflammasome assembly. Tranilast markedly suppressed NLRP 3 inflammasome activation in low‐density lipoprotein receptor– and apolipoprotein E–deficient macrophages. Through reconstitution of the NLRP 3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP 3 inflammasome activation. By adopting different regimens for tranilast treatment of low‐density lipoprotein receptor– and apolipoprotein E–deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP 3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP 3 ubiquitination, blunts the assembly and activation of the NLRP 3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low‐density lipoprotein receptor– and apolipoprotein E–deficient mice.

NLRP3 inflammasome in endothelial dysfunction

“…Additionally, CY-09, OLT1177, 3,4-methylenedioxy-β-nitrostyrene (MNS), N-[3′,4′-dimethoxycinnamoyl]-anthranilic acid (Tranilast), and oridonin are also specific inhibitors of NLRP3 inflammasome 33 , 117 . Remarkably, a recent study found that tranilast exhibited antivascular inflammation and anti-atherosclerosis properties via increasing NLRP3 ubiquitination and impeding NLRP3 inflammasome activation 118 . Besides, oridonin was found to blunt endothelial inflammation through restraining the activation of MAPK and NF-κB signaling pathways 119 .…”

Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules

“…Tranilast, a tryptophan metabolite analog, binds to NACHT domain of NLRP3, preventing NLRP3-NLRP3 interaction and alleviating the symptoms of gouty arthritis, cryopyrin-associated autoinflammatory syndromes, and type 2 diabetes ( 115 ). In addition, tranilast increases K63-linked ubiquitination of NLRP3 ( 116 ).…”

The Role of miRNA-146a and Proinflammatory Cytokines in Carotid Atherosclerosis

“…On the one hand, the inflammatory reaction can promote the rupture of foam cells after phagocytosis of lipids, releasing more lipid content that accelerates the increase in the atherosclerotic core volume; on the other hand, the inflammatory reaction can also cause carotid vascular remodeling, which leads to further narrowing of the vascular lumen. Studies have shown that administration of tranilast in an animal model of vascular stenosis can reduce vascular remodeling and thus improve vascular stenosis [ 13 ].…”