title: Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway.
abstract: Although it has been established that myocyte enhancer factor 2 (MEF2) plays pivotal roles in the development of the cardiovascular system as well as skeletal muscle cells, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To investigate the role of MEF2 in vascular inflammation and that of p38 in the activation of MEF2, we infected cultured rat vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a dominant-negative mutant of MEF2A (MEF2ASA) or mitogen-activated protein kinase kinase 6 (MEK6AA), and examined their effects on the expression of monocyte chemoattractant protein-1 (MCP-1), which is known to play important roles in vascular inflammation. We also examined the role of MEF2 in vivo using a rat model of transluminal wire-induced injury of the femoral artery. Angiotensin II (Ang II)-induced expression of MCP-1 mRNA was significantly inhibited by infection with adenoviruses encoding MEF2ASA (AdMEF2ASA) or MEK6AA. Ang II-induced increase of MCP-1 promoter activity was also significantly suppressed by overexpression of MEF2ASA or MEK6AA. Ang II stimulated the transactivating function of MEF2A and this activation was inhibited by overexpression of MEK6AA. Infection with AdMEF2ASA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. AdMEF2ASA infection also inhibited macrophages infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that MEF2 activation via the p38-dependent pathway mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophages infiltration.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. suzuki-2im@h.u-tokyo.ac.jp
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satonaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Oba
authors.forename: Ryo
authors.initials: R
authors.lastname: Takeda
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D007249:Inflammation / Q000209:etiology; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors; D008264:Macrophages / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D051381:Rats; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases