NLRP3 Inflammasome Activation Controls Vascular Smooth Muscle Cells Phenotypic Switch in Atherosclerosis

International Journal of Molecular Sciences

卷:23

Fabienne Burger¹  Rafaela Fernandes da Silva¹  François Mach¹  Karim J. Brandt¹  Daniela Baptista¹  Aline Roth¹  Kapka Miteva¹  Fabrizio Montecucco² 

[1] Division of Cardiology, Foundation for Medical Research, Department of Medicine, Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211 Geneva, Switzerland;

[2] Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy;

关键词: NLRP3 inflammasome activation;    vascular smooth muscle;    vascular smooth muscle phenotypic switch;    atherosclerosis;    atherosclerosis plaques stability;   

DOI  :  10.3390/ijms23010340

来源: DOAJ

【 摘 要 】

(1) Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced α-SMA, SM22α, Oct-4, and upregulation of KLF-4 and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1β secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1β in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis.

【 授权许可】

Unknown