Abstract
Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.
Highlights
Vascular smooth muscle cells (VSMCs) are a dominant cellular constituent of arteries and a critical determinant of vascular disease.[1]
It is not known whether Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is activated in the VSMCs of spontaneously hypertensive rats (SHR), and whether the inflammasome activation contributes to VSMC phenotypic transformation and proliferation as well as vascular remodeling in hypertension
Immunofluorescence double staining showed that NLRP3 immunoreactivity in aortic media was increased in SHR compared with WKY (Figure 1a)
Summary
Vascular smooth muscle cells (VSMCs) are a dominant cellular constituent of arteries and a critical determinant of vascular disease.[1]. Unlike skeletal muscle cells and cardiocytes with terminally differentiated feature, VSMCs may preserve phenotype alterations from a differentiated phenotype (contractile phenotype) to a dedifferentiated phenotype (synthetic phenotype) in response to various stimuli.[3] The phenotypic transformation from differentiated to dedifferentiated VSMCs is involved in reduced expression of contractile proteins, and increased production of extracellular matrix and expression of inflammatory cytokines.[4] It serves as a major initiating factor for vascular remodeling in several cardiovascular diseases such as atherosclerosis, hypertension, vascular stenosis and diabetic vascular complications.[3]. The effects of NLRP3 gene silencing on hypertension and vascular remodeling were investigated in SHR
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