Vascular Lipolysis: A Determinant of Atherosclerosis

血管脂肪分解：动脉粥样硬化的决定因素

• 批准号: 6369438
• 负责人: David Yiu-Kwan Hui
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6369438
• 关键词: atherosclerosis; carboxylic ester hydrolases; ceramides; dietary lipid; gene expression; genetic polymorphism; genetic screening; genetic strain; genetic susceptibility; genetically modified animals; isozymes; laboratory mouse; lipase; lipid metabolism; lipolysis; low density lipoprotein; low density lipoprotein receptor; lysolecithins; molecular pathology; nutrition related tag; oxidized lipid; pathogenic diet; site directed mutagenesis; vascular endothelium

DESCRIPTION (provided by applicant): Recent studies have clearly documented the importance of phospholipid and sphingolipid metabolites in atherosclerosis and vascular biology. While enzymes responsible for phospholipid and sphingomyelin hydrolysis in the vessel wall have been identified and were shown to contribute to atherogenesis, enzyme(s) responsible for lowering the level of their hydrolytic products, the bioactive lysophosphatidylcholine (LysoPC) and ceramide, have not been characterized to date. Results generated from this laboratory revealed the presence of the pancreatic-type carboxyl ester lipase (CEL) in human vascular wall. This protein is synthesized by aortic endothelial cells and monocyte-derived macrophages in a manner inducible by oxidized LDL (oxLDL). Importantly, CEL displayed avid bile salt-independent lysoPC and ceramide hydrolytic activities. Human CEL is also highly polymorphic, encoding proteins varying in the number of proline-rich repeating units at the carboxyl terminus. Based on these novel observations, this application proposes to test the following hypotheses: (1) CEL expression in the vasculature is an inflammatory response mechanism that protects early stages of atherogenesis by hydrolyzing and reducing the atherogenic properties of lysoPC and ceramide; (2) the number of proline-rich repeating units in the C-terminus of CEL is important in determining its ability to hydrolyze lysoPC and ceramide; and (3) CEL gene polymorphism is a determinant of individual susceptibility to modified-LDL mediated atherogenic events. These hypotheses viii be tested by experiments under 3 specific aims. Specific Aim 1 plans to produce vascular-specific CEL transgenic mice to evaluate the impact of vascular CEL gene expression on initiation and progression of the atherosclerotic plaque. Specific Aim 2 will use site-directed mutagenesis approach to test the hypothesis that the number of proline-rich repeating units at its C-terminus is an important determinant of lysoPC and ceramide hydrolytic activities of CEL, and thus the effectiveness of different CEL isoforms in protecting vascular cells against lysoPC- and ceramide-induced atherogenic events. Specific Aim 3 will identify the mechanism by which modified LDL induces CEL gene expression in human macrophages and endothelia cells. Experiments will be designed to test the hypothesis that CEL gene activation is mediated via signal transduction mechanisms as a consequence of oxLDL binding to scavenger receptors on the cell surface, or alternatively requires the internalization of specific lipid constituents associated with oxidized lipoproteins. Taken together, these studies will identify novel factors that contribute to determining atherosclerosis susceptibility. Genetic screening strategy may also be designed to identify subjects predispose to atherosclerosis for early intervention and reducing their risk of developing this disease.

描述（由申请人提供）：最近的研究已经清楚地证明了磷脂和鞘脂代谢物在动脉粥样硬化和动脉粥样硬化中的重要性