2. Academic Validation
  3. circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells

circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells

  • Cell Mol Life Sci. 2023 Jul 27;80(8):229. doi: 10.1007/s00018-023-04840-6.
Yang Bai 1,  Long Zhang 1,  Bin Zheng 1,  Xinhua Zhang 1 2,  Hong Zhang 3,  Anning Zhao 4,  Jing Yu 5,  Zhan Yang 3,  Jinkun Wen 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China.
  • 2 Institution of Chinese Integrative Medicine, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China.
  • 3 Molecular Biology Laboratory, Talent and Academic Exchange Center, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050017, China.
  • 4 Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050017, China.
  • 5 Department of Respiratory, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050017, China.
  • 6 Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China. wjk@hebmu.edu.cn.
PMID: 37498354 DOI: 10.1007/s00018-023-04840-6
Abstract

circACTA2 derived from the smooth muscle α-actin gene plays an important role in the regulation of vascular smooth muscle cell (VSMC) phenotype. The activation of NLRP3 inflammasome is involved in VSMC phenotypic switching. However, the mechanistic relationship between circACTA2 and NLRP3 inflammasome during vascular remodeling remains poorly understood. Here, we showed that circACTA2 was down-regulated in human intimal hyperplasia. circACTA2 overexpression in circACTA2 transgenic mice significantly decreased the neointimal hyperplasia induced by vascular injury, which is concomitant with a decrease in IL-18, IL-1β, TNF-α, and IL-6 levels. Gain- and loss-of-function studies revealed that circACTA2 alleviated VSMC inflammation by suppressing the activation of NLRP3 inflammasome. Mechanistically, circACTA2 inhibited the expression of NF-κB p65 and p50 subunits and interacted with p50, which impedes the formation of the p50/p65 heterodimer and nuclear translocation induced by TNF-α, thus resulting in the suppression of NLRP3 gene transcription and inflammasome activation. Furthermore, circACTA2 overexpression mitigated inflammation via repressing NLRP3 inflammasome-mediated VSMC Pyroptosis. Importantly, employing a decoy oligonucleotide to compete with circACTA2 for binding to p50 could attenuate the expression of NLRP3, ASC, and Caspase-1. These findings provide a novel insight into the functional roles of circACTA2 in VSMCs, and targeting the circACTA2-NF-κB-NLRP3 axis represents a promising therapeutic strategy for vascular remodeling.

Keywords

Inflammation; NF-κB; NLRP3; VSMC; Vascular remodeling; circACTA2.

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