Yu Carol, Luo Xiaoyan, Farhat Nada, Daneault Caroline, Duquette Natacha, Martel Cécile, Lambert Jean, Thorin-Trescases Nathalie, Rosiers Christine Des, Thorin Eric
Departments of Pharmacology and Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada (C.Y., N.F., T.) Montreal Heart Institute, Research Center, Montreal, Quebec, Canada (C.Y., X.L., N.F., C.D., N.D., M., N.T.T., C.D.R., T.).
Montreal Heart Institute, Research Center, Montreal, Quebec, Canada (C.Y., X.L., N.F., C.D., N.D., M., N.T.T., C.D.R., T.).
J Am Heart Assoc. 2014 Aug 15;3(4):e001024. doi: 10.1161/JAHA.114.001024.
Angiopoietin-like-2 (angptl2) is produced by several cell types including endothelial cells, adipocytes and macrophages, and contributes to the inflammatory process in cardiovascular diseases. We hypothesized that angptl2 impairs endothelial function, and that lowering angptl2 levels protects the endothelium against high-fat diet (HFD)-induced fat accumulation and hypercholesterolemia.
Acute recombinant angptl2 reduced (P<0.05) acetylcholine-mediated vasodilation of isolated wild-type (WT) mouse femoral artery, an effect reversed (P<0.05) by the antioxidant N-acetylcysteine. Accordingly, in angptl2 knockdown (KD) mice, ACh-mediated endothelium-dependent vasodilation was greater (P<0.05) than in WT mice. In arteries from KD mice, prostacyclin contributed to the overall dilation unlike in WT mice. After a 3-month HFD, overall vasodilation was not altered, but dissecting out the endothelial intrinsic pathways revealed that NO production was reduced in arteries isolated from HFD-fed WT mice (P<0.05), while NO release was maintained in KD mice. Similarly, endothelium-derived hyperpolarizing factor (EDHF) was preserved in mesenteric arteries from HFD-fed KD mice but not in those from WT mice. Finally, the HFD increased (P<0.05) total cholesterol-to-high-density lipoprotein ratios, low-density lipoprotein-to-high-density lipoprotein ratios, and leptin levels in WT mice only, while glycemia remained similar in the 2 strains. KD mice displayed less triglyceride accumulation in the liver (P<0.05 versus WT), and adipocyte diameters in mesenteric and epididymal white adipose tissues were smaller (P<0.05) in KD than in WT fed an HFD, while inflammatory gene expression increased (P<0.05) in the fat of WT mice only.
Lack of angptl2 expression limits the metabolic stress induced by an HFD and maintains endothelial function in mice.
血管生成素样蛋白2（Angptl2）由包括内皮细胞、脂肪细胞和巨噬细胞在内的多种细胞类型产生，并参与心血管疾病的炎症过程。我们推测Angptl2会损害内皮功能，降低Angptl2水平可保护内皮免受高脂饮食（HFD）诱导的脂肪堆积和高胆固醇血症的影响。
急性给予重组Angptl2可降低（P<0.05）分离的野生型（WT）小鼠股动脉中乙酰胆碱介导的血管舒张，抗氧化剂N-乙酰半胱氨酸可逆转这一效应（P<0.05）。相应地，在Angptl2基因敲低（KD）小鼠中，乙酰胆碱介导的内皮依赖性血管舒张比WT小鼠更强（P<0.05）。与WT小鼠不同，KD小鼠动脉中的前列环素对总体血管舒张有贡献。高脂饮食3个月后，总体血管舒张未改变，但剖析内皮固有途径发现，高脂饮食喂养的WT小鼠分离的动脉中一氧化氮（NO）生成减少（P<0.05），而KD小鼠中NO释放得以维持。同样，高脂饮食喂养的KD小鼠肠系膜动脉中的内皮衍生超极化因子（EDHF）得以保留，而WT小鼠则没有。最后，高脂饮食仅使WT小鼠的总胆固醇与高密度脂蛋白比值、低密度脂蛋白与高密度脂蛋白比值以及瘦素水平升高（P<0.05），而两品系的血糖水平保持相似。KD小鼠肝脏中的甘油三酯堆积较少（与WT相比，P<0.05），高脂饮食喂养的KD小鼠肠系膜和附睾白色脂肪组织中的脂肪细胞直径比WT小鼠小（P<0.05），而仅WT小鼠脂肪中的炎症基因表达增加（P<0.05）。
缺乏Angptl2表达可限制高脂饮食诱导的代谢应激并维持小鼠的内皮功能。
