title: Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation.
abstract: Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satonaka
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
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: Atsuo
authors.initials: A
authors.lastname: Goto
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 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000503:physiopathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2; D016572:Cyclosporine / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D007093:Imidazoles / Q000494:pharmacology; D048669:MAP Kinase Kinase 6; D008264:Macrophages / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D017539:Tunica Intima / Q000473:pathology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014657:Vasculitis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
chemical_list: C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007093:Imidazoles; D011506:Proteins; D011725:Pyridines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D016572:Cyclosporine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D019703:Calcineurin; D014633:Valine; C093642:SB 203580