Pathophysiological significance of cylindromatosis in the vascular endothelium and macrophages for the initiation of age-related atherogenesis |
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Authors: | Yuki Imaizumi Yoichi Takami Koichi Yamamoto Motonori Nagasawa Yoichi Nozato Satoko Nozato Hikari Takeshita Cheng Wang Serina Yokoyama Hiroki Hayashi Kazuhiro Hongyo Hiroshi Akasaka Yasushi Takeya Ken Sugimoto Hironori Nakagami Hiromi Rakugi |
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Affiliation: | 1. Department of Geriatric and General Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan;2. Department of Health Development and Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan |
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Abstract: | Cardiovascular disease is one of the leading causes of death in the elderly, and novel therapeutic targets against atherogenesis are urgent. The initiation of atherosclerotic changes of monocyte adhesion on the vascular endothelium and subsequent foam cell formation are noteworthy pathophysiologies when searching for strategies to prevent the progression of age-related atherosclerosis. We report the significance of the deubiquitinating enzyme cylindromatosis (CYLD) in vascular remodeling by interference with inflammatory responses regulated by NF-κB signaling. The purpose of this study was to elucidate the pathological functions of CYLD in the early phase of atherogenesis associated with aging.Treatment with inflammatory cytokines induced endogenous CYLD in aortic endothelial cells (HAECs) and THP-1?cells. siRNA-mediated CYLD silencing led to enhanced monocyte adhesion along with increased adhesion molecules in HAECs treated with TNFα. In siRNA-mediated CYLD silenced RAW 264.7 macrophages treated with oxidized LDL (oxLDL), augmented lipid accumulation was observed, along with increased expression of the class A macrophage scavenger receptor (SR-A), lectin-like oxidized LDL receptor-1 (LOX-1), CD36, fatty acid binding protein 4 (FABP4), the cholesterol ester synthase acyl-CoA cholesterol acyltransferase (ACAT1), MCP-1, and IL-1β and decreased expression of scavenger receptor class B type I (SR-BI). Intriguingly, CYLD gene expression was significantly reduced in bone marrow-derived macrophages of aged mice compared that of young mice, as well as in senescent HAECs compared with young cells.These findings suggest that age-related attenuation of CYLD expression in endothelial cells (ECs) and macrophages triggers the initiation of age-related atherogenesis by exacerbating monocyte adhesion on the endothelium and foam cell formation. CYLD in the vasculature may be a novel therapeutic target, especially in the early preventive intervention against the initiation of age-related atherogenesis. |
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Keywords: | CYLD Aging Macrophage Endothelial cell Inflammation Foam cell CYLD cylindromatosis HAECs aortic endothelial cells oxLDL oxidized LDL ECs endothelial cells SR-A the class A macrophage scavenger receptor LOX-1 lectin-like oxidized LDL receptor-1 FABP4 fatty acid binding protein 4 SR-BI scavenger receptor class B type I UCHL1 ubiquitin carboxyl-terminal hydrolase L1 HCASMCs human coronary aortic smooth muscle cells BMDM marrow-derived macrophage NOX4 nicotinamide adenine dinucleotide phosphate oxidase 4 NCEH neutral cholesteryl ester hydrolase |
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