casein-kinase-ii and Neointima

Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation.. The ligation injury model of Sirt1-Tg/Sm22α-/- mice displayed an increased level of the inflammatory molecules in the carotid arteries compared with Sirt1-Tg mice, accompanied with aggravating neointimal hyperplasia. In the in vitro study, on the one hand, we showed that TNF-α induced the epigenetic silencing of SM22α transcription via EZH2-mediated H3K27 methylation in the SM22α promoter region, contributing to inflammatory response. On the other hand, TNF-α simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22α transcription by inhibiting EZH2 activity. Increased SM22α in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1.. Our findings demonstrate that, in response to TNF-α stimulation, CKII-SIRT1-SM22α acts in a loop to reinforce the expression of SM22α, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22α to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.

Topics: Acetylation; Animals; Carotid Artery Injuries; Casein Kinase II; Cells, Cultured; Disease Models, Animal; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Enzyme Activation; Genotype; Histones; Humans; Hyperplasia; Inflammation; Male; Mice, Knockout; Mice, Transgenic; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Phenotype; Phosphorylation; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1; Transcription, Genetic; Tumor Necrosis Factor-alpha

Neointimal hyperplasia is a product of VSMC replication and consequent accumulation within the blood vessel wall. In this study, we determined whether inhibition of protein kinase CK2 and the resultant stabilisation of proline-rich homeodomain (PRH) could suppress VSMC proliferation. Both silencing and pharmacological inhibition of CK2 with K66 antagonised replication of isolated VSMCs. SiRNA-induced knockdown as well as ectopic overexpression of proline-rich homeodomain indicated that PRH disrupts cell cycle progression. Mutation of CK2 phosphorylation sites Ser

Topics: Animals; Casein Kinase II; Cell Cycle Checkpoints; Cell Proliferation; Cells, Cultured; Homeodomain Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hyperplasia; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Neointima; Phosphorylation; Proline-Rich Protein Domains; Protein Kinase Inhibitors; Rats; RNA Interference; Saphenous Vein; Signal Transduction; Tissue Culture Techniques; Transcription Factors; Transfection