title: Roles of the kinase TAK1 in CD40-mediated effects on vascular oxidative stress and neointima formation after vascular injury.
abstract: Although TAK1 has been implicated in inflammation and oxidative stress, its roles in vascular smooth muscle cells (VSMCs) and in response to vascular injury have not been investigated. The present study aimed to investigate the role of TAK1 in modulating oxidative stress in VSMCs and its involvement in neointima formation after vascular injury. Double immunostaining reveals that vascular injury induces a robust phosphorylation of TAK1 (Thr187) in the medial VSMCs of injured arteries in wildtype mice, but this effect is blocked in CD40-deficient mice. Upregulation of TAK1 in VSMCs is functionally important, as it is critically involved in pro-oxidative and pro-inflammatory effects on VSMCs and eventual neointima formation. In vivo, pharmacological inhibition of TAK1 with 5Z-7-oxozeaenol blocked the injury-induced phosphorylation of both TAK1 (Thr187) and NF-kB/p65 (Ser536), associated with marked inhibition of superoxide production, 3-nitrotyrosine, and MCP-1 in the injured arteries. Cell culture experiments demonstrated that either siRNA knockdown or 5Z-7-oxozeaenol inhibition of TAK1 significantly attenuated NADPH oxidase activation and superoxide production induced by CD40L/CD40 stimulation. Co-immunoprecipitation experiments indicate that blockade of TAK1 disrupted the CD40L-induced complex formation of p22phox with p47phox, p67phox, or Nox4. Blockade of TAK1 also inhibited CD40L-induced NF-kB activation by modulating IKKα/β and NF-kB p65 phosphorylation and this was related to reduced expression of proinflammatory genes (IL-6, MCP-1 and ICAM-1) in VSMCs. Lastly, treatment with 5Z-7-oxozeaenol attenuated neointimal formation in wire-injured femoral arteries. Our findings demonstrate previously uncharacterized roles of TAK1 in vascular oxidative stress and the contribution to neointima formation after vascular injury.
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America; Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Zifang
authors: Z
authors: Song
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors: Xiaolei
authors: X
authors: Zhu
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors: Rong
authors: R
authors: Jin
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America; Department of Cardiology, The Affiliated Hospital of Jiangsu University, Jiangsu, Zhenjiang, China.
authors: Cuiping
authors: C
authors: Wang
authors: Department of Cardiology, The Affiliated Hospital of Jiangsu University, Jiangsu, Zhenjiang, China.
authors: Jinchuan
authors: J
authors: Yan
authors: Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Qichang
authors: Q
authors: Zheng
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors: Anil
authors: A
authors: Nanda
authors: Department of Physiology, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors: D Neil
authors: DN
authors: Granger
authors: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America; Department of Physiology, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors: Guohong
authors: G
authors: Li
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D019255:NADPH Oxidases; D058426:Neointima / Q000201:enzymology*; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D057772:Vascular System Injuries / Q000201:enzymology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D019013:CD40 Antigens; D020930:MAP Kinase Kinase Kinases; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D000099151:MAP Kinase Kinase Kinase 7