title: Relation between anti-atherosclerotic effects of IRAK4 and modulation of vascular smooth muscle cell phenotype in diabetic rats.
abstract: Deregulation of phenotypic modulation in VSMCs is the initial stage of atherosclerosis, especially in diabetes. Functional deficiency of IRAK4 inhibits the formation of vascular lesions in ApoE-/- mice. Therefore, in this study, we examined the functions of IRAK4 in the regulation of VSMCs differentiation and phenotypic modulation at the levels of transcription and translation in T2D rats. The T2D rat model was generated by feeding a high-fat diet and injecting a low dose of streptozotocin intraperitoneally. VSMCs were isolated from the thoracic aortas of the T2D rats. VSMCs proliferation and migration were measured using water soluble tetrazolium salt-1 assay, 5-ethynyl-29-deoxyuridine staining and migration assay. IRAK4 was knocked down by siRNA and inhibited by an IRAK1/4 inhibitor. The mRNAs and proteins of signal molecules and phenotypic markers were detected by qRT-PCR and western blotting. The results demonstrated that LPS significantly increased viability, cell migration rate and amount of DNA in VSMCs. The IRAK4 inhibitor also reduced LPS-mediated protein expression of myosin heavy chain and nuclear factor κB p65 subunit and increased smooth muscle 22α expression. Moreover, IRAK4 knock-down reduced the LPS-mediated expression of mRNAs for myosin heavy chain, nuclear factor κB p65 subunit, and monocyte chemoattractant protein-1 (MCP-1), but increased the mRNA of smooth muscle 22α in VSMCs. The activation of IRAK4 phenotypically modulated VSMCs from differentiation to dedifferentiation. Inactivation of IRAK4 exerts a protective effect on VSMCs differentiation and inhibits inflammation. IRAK4 could therefore be a target for interventions to prevent and treat the initial phase of atherosclerosis.
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College 84 West Huaihai Road, Xuzhou, Jiangsu, Peoples Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Cardiology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Defeng
authors.initials: D
authors.lastname: Pan
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College84 West Huaihai Road, Xuzhou, Jiangsu, Peoples Republic of China; Department of Cardiology, Affiliated Hospital of Xuzhou Medical College99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cardiology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College 84 West Huaihai Road, Xuzhou, Jiangsu, Peoples Republic of China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Tongda
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou 221002, Jiangsu, Peoples Republic of China.
authors.forename: Wanling
authors.initials: W
authors.lastname: Wu
keywords: IRAK4; MCP-1; Type 2 diabetes rat model; Vascular smooth muscle cells; phenotypic modulation