Abstract
(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.
Highlights
Cardiovascular diseases (CVD) are still the predominant cause of death and morbidity, with atherosclerosis as the main underlying cause [1]
60% to 70% of foam cells in atherosclerotic lesions are of VSMC, not leukocyte origin, but whether Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation plays a role in VSMC phenotypic switch is not known
VSMCs were isolated from the aortic arch of 8 to 12 weeks old C57BL/6 mice and after VSMCs expansion, the phenotype and purity were confirmed by staining with antimouse α-SMA, SM22α, and CD31 and CD90
Summary
Cardiovascular diseases (CVD) are still the predominant cause of death and morbidity, with atherosclerosis as the main underlying cause [1]. 60% to 70% of foam cells in atherosclerotic lesions are of VSMC, not leukocyte origin, but whether NLRP3 inflammasome activation plays a role in VSMC phenotypic switch is not known. Since NLRP3 inflammasome activation was shown to be an important mechanism driving atherogenesis, inflammation, and foam cell formation, it could emerge as a crucial mechanism triggering VSMC phenotypic switch and subsequently plaque destabilization. Until now, this hypothesis has not been investigated and it could open a door to the revelation of a new mechanism in vascular pathology
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