title: Apoptosis signal-regulating kinase 1 deficiency attenuates vascular injury-induced neointimal hyperplasia by suppressing apoptosis in smooth muscle cells.
abstract: Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tasaki
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nabeshima
authors.forename: Shohei
authors.initials: S
authors.lastname: Kitada
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Noguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000077214:Becaplermin; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006965:Hyperplasia; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008026:Ligation; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D058426:Neointima / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D020574:Proto-Oncogene Proteins c-sis; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse