Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

Watanabe, Takuya; Suguro, Toshiaki; Kanome, Tomoko; Sakamoto, Yuichiro; Kodate, Syuusuke; Hagiwara, Takaaki; Hongo, Shigeki; Hirano, Tsutomu; Adachi, Mitsuru; Miyazaki, Akira

doi:10.1161/01.hyp.0000184226.99196.b5

Cited by 101 publications

(100 citation statements)

References 49 publications

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“…UII and its receptor have both been linked to macrophage function, particularly the formation of foam cells [12]. This is consistent with our findings of increased CCL2 expression and monocyte adhesion in vitro, and the attenuation of these effects with UT antagonism in a high-glucose environment.…”

Section: Discussionsupporting

confidence: 92%

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Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

et al. 2013

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Aims/hypothesis The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. Methods Endothelial cells were grown in normal-and highglucose (5 and 25 mmol/l) media with and without UII (10 −8 mol/l) and/or the UII receptor antagonist, SB-657510 (10 −8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mgkg −1 day −1 ; n=20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. Results In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. Conclusions/interpretation This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

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Section: Discussionsupporting

confidence: 92%

“…Additionally, chronic UII infusion has been shown to enhance macrophage foam cell formation [12] and atherosclerosis in high-fat-fed Apoe knockout (KO) mice [13]. While UT antagonism has been investigated in diabetic nephropathy [14,15], little is known of the role of UII in the development of diabetes-associated atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

et al. 2013

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“…Other laboratories have shown that the cytokine transforming growth factor-b1 (TGF-b1) also increases ACAT1 activity in human monocytes (43). In addition, urotensin II, the potent vasoconstrictor peptide that leads to hypertension and atherosclerosis in humans, was shown to upregulate the ACAT1 gene expression in human macrophages (44). In contrast, the human ACAT1 gene expression was downregulated by adiponectin, an adipocytokine that exerts many antiatherosclerotic effects in cell culture studies (45).…”

Section: Discussionmentioning

confidence: 99%

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

Lei

Xiong

Chen

et al. 2009

Journal of Lipid Research

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High levels of the inflammatory cytokine tumor necrosis factor-a (TNF-a) are present in atherosclerotic lesions. TNF-a regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-a may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-a enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-a. Our data demonstrate that TNF-a, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-a is proatherosclerotic during early phase of lesion development.-Lei, L., Y.

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“…Levels of U and UT expression are up-regulated by inflammatory cytokines, such as interferon-, IL-6, and IL-1 , and by hypoxia (ischemia) and mechanical stimuli [34][35][36][37] . U contributes to the development of atherosclerosis by inducing macrophage foam cell formation, EC and VSMC proliferation, and extracellular matrix production 14,38,39) . U accelerates macrophage foam cell formation by up-regulating acyl-CoA:cholesterol acyltransferase-1 38) , and has synergistic interactions with mildly oxidized LDL in inducing VSMC proliferation at the highest rate among vasoactive agents 40) .…”

Section: Vsmc Mø Mømentioning

confidence: 99%

“…U contributes to the development of atherosclerosis by inducing macrophage foam cell formation, EC and VSMC proliferation, and extracellular matrix production 14,38,39) . U accelerates macrophage foam cell formation by up-regulating acyl-CoA:cholesterol acyltransferase-1 38) , and has synergistic interactions with mildly oxidized LDL in inducing VSMC proliferation at the highest rate among vasoactive agents 40) . Our recent study showed that chronic infusion of U into apoE-knockout mice enhances atherosclerotic lesions 41) .…”

Section: Vsmc Mø Mømentioning

confidence: 99%

Increased Plasma Urotensin-II and Carotid Atherosclerosis are Associated with Vascular Dementia

Ban

Watanabe

Suguro

et al. 2009

JAT

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Aim: Human urotensin-(U ) is a cyclic neuropeptide with potent vasoconstrictive activity in the vasculature. The expression of U and its receptor (UT) mRNA is detected at high levels in the brain. We evaluated the relationship between plasma U levels and vascular dementia (VaD) caused by stroke or atherosclerotic small vessel disease. Methods: Carotid artery intima-media thickness (IMT), plaques, plasma levels of immunoreactive U (IR-U ), and atherosclerotic biomarkers were determined in 42 patients with VaD, 197 with Alzheimer's disease (AD), and 47 non-demented elderly controls. Results: Age, gender, body mass index, systolic blood pressure (SBP), fasting plasma glucose, insulin, triglycerides, high-density lipoprotein cholesterol, leptin, and plasminogen activator inhibitor-1 levels were not significantly different among these groups. IR-U , low-density lipoprotein (LDL) cholesterol, lipoprotein(a), lipid peroxides, interleukin-6, and high-sensitive C-reactive protein (hs-CRP) levels, and maximum IMT were significantly higher in VaD than in AD patients or controls. IR-U level showed a significantly positive correlation with SBP or maximum IMT. Multivariate logistic regression analysis revealed a significantly independent association between IR-U levels or increased maximum IMT ( ≥ 1.1 mm) and VaD as compared with SBP, LDL cholesterol, and interleukin-6 levels. Conclusion: Increased plasma IR-U levels and carotid atherosclerosis may be involved in the pathogenesis and progression of VaD.

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Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

Cited by 101 publications

References 49 publications

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

Increased Plasma Urotensin-II and Carotid Atherosclerosis are Associated with Vascular Dementia

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