title: Stimulatory effects of cardiotrophin 1 on atherosclerosis.
abstract: Cardiotrophin 1 (CT-1), an interleukin-6 family cytokine, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates proatherogenic molecule expression in human vascular endothelial cells and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation and vascular smooth muscle cell migration and proliferation in vitro, and on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE(-/-)) mice in vivo. CT-1 was expressed at high levels in endothelial cells and macrophages in both humans and ApoE(-/-) mice. CT-1 significantly enhanced oxidized low-density lipoprotein-induced foam cell formation associated with increased levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 expression in human monocyte-derived macrophages. CT-1 significantly stimulated the migration, proliferation, and collagen-1 expression in human aortic vascular smooth muscle cells. Four-week infusion of CT-1 into ApoE(-/-) mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration, vascular smooth muscle cell proliferation, and collagen-1 content in the aortic wall. Activation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, nuclear factor κB, and cyclooxygenase-2, was observed in exudate peritoneal macrophages from ApoE(-/-) mice infused with CT-1. Infusion of anti-CT-1-neutralizing antibody alone into ApoE(-/-) mice significantly suppressed monocyte/macrophage infiltration in atherosclerotic lesions. These results indicate that CT-1 accelerates the development of atherosclerotic lesions by stimulating the inflammasome, foam cell formation associated with CD36 and acyl-CoA:cholesterol acyltransferase-1 upregulation in macrophages, and migration, proliferation, and collagen-1 production in vascular smooth muscle cells.
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan. watanabe@toyaku.ac.jp.
authors.forename: Hanae
authors.initials: H
authors.lastname: Konii
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Hazuki
authors.initials: H
authors.lastname: Okiyama
authors.forename: Rena
authors.initials: R
authors.lastname: Watanabe
authors.forename: Akinori
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Keigo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Fumiko
authors.initials: F
authors.lastname: Itoh
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D024042:Collagen Type I; D016207:Cytokines; C092073:cardiotrophin 1
keywords: atherosclerosis; cardiotrophin 1; hypertension; macrophages; smooth muscle