title: Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice.
abstract: Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE(-/-)) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE(-/-) mice. ApoE(-/-)Adamts4(-/-) double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE(-/-) mice.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
authors.forename: Saran
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
authors.forename: Fiona H S
authors.initials: FH
authors.lastname: Wong
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
authors.forename: Chung Wee
authors.initials: CW
authors.lastname: Thiam
authors.affiliation: Cancer Science Institute of Singapore, Singapore, 117599, Singapore.
authors.forename: Md Zakir
authors.initials: MZ
authors.lastname: Hossain
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Department of Cardiology, National University Heart Centre, National University Health System, Singapore 119228, Singapore.
authors.forename: Kian Keong
authors.initials: KK
authors.lastname: Poh
authors.affiliation: Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirohata
authors.affiliation: Department of General Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical sciences, Okayama University, Okayama 700-8558, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
authors.forename: Véronique
authors.initials: V
authors.lastname: Angeli
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
authors.forename: Ruowen
authors.initials: R
authors.lastname: Ge
mesh_terms: D000071121:ADAMTS4 Protein / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control; D059305:Diet, High-Fat; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic
chemical_list: D001057:Apolipoproteins E; D000071121:ADAMTS4 Protein; C000603919:Adamts4 protein, mouse