Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes
Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes
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DOI：
10.1093/cvr/cvs136
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发表时间：
2012-06-01
影响因子：
10.8
通讯作者：
Llorente-Cortes, Vicenta
中科院分区：
文献类型：
--
作者：
Cal, Roi;Castellano, Jose;Llorente-Cortes, Vicenta
心肌在缺血条件下积聚细胞内脂质，并且心肌脂肪沉积与心功能不全密切相关。本研究旨在分析缺氧对新生大鼠心室肌细胞（NRVM）和心肌源性HL-1细胞低密度脂蛋白受体相关蛋白1（LRP 1）表达的影响及其分子机制，探讨LRP 1在缺氧心肌细胞摄取极低密度脂蛋白（VLDL）中的作用，采用在体猪急性心肌梗死模型，研究低氧对脂蛋白受体表达和心肌脂质谱的影响，脂质提取后的薄层层析显示，VLDL暴露导致胆固醇酯（CE）和甘油三酯（TG）在HL-1细胞中，低氧条件进一步增加了VLDL衍生的细胞内脂质积累。通过慢病毒介导的干扰RNA敲低LRP 1特异性阻止HL-1细胞和NRVM中缺氧诱导的VLDL CE内化。脂多糖（LPS）诱导的LRP 1过表达特异性增加NRVM中的VLDL-CE蓄积。此外，使用双放射性标记的[H-3]CE-[C-14]TG-VLDL，我们发现LRP 1缺陷特异性地阻止缺氧诱导的VLDL-[H-3]CE摄取。最后，在猪的心肌梗死模型中，缺血区表现出LRP 1蛋白上调和心肌内CE过度accumulation.Our结果表明，缺氧增加LRP 1表达通过HIF-1和LRP 1过表达介导缺氧诱导的VLDL-CE摄取和积累在心肌细胞。
The myocardium accumulates intracellular lipids under ischaemic conditions, and myocardial fat deposition is closely associated with cardiac dysfunction. Our aims were to analyse the effect of hypoxia on low-density lipoprotein receptor-related protein 1 (LRP1) expression in neonatal rat ventricular myocytes (NRVM) and cardiac-derived HL-1 cells and the molecular mechanisms involved in this effect, to determine the role of LRP1 in the very low density lipoprotein (VLDL) uptake by hypoxic cardiomyocytes, and to study the effect of hypoxia on lipoprotein receptor expression and myocardial lipid profile in an in vivo porcine experimental model of acute myocardial infarction.Thin-layer chromatography after lipid extraction showed that VLDL exposure leads to cholesteryl ester (CE) and triglyceride (TG) accumulation in a dose-dependent manner and that hypoxic conditions further increased VLDL-derived intracellular lipid accumulation in HL-1 cells. Knockdown of LRP1 through lentiviral-mediated interfering RNA specifically prevented hypoxia-induced VLDL-CE internalization in HL-1 cells and NRVM. Lipopolysaccharide (LPS)-induced LRP1 overexpression specifically increased VLDL-CE accumulation in NRVM. In addition, using double-radiolabelled [H-3]CE-[C-14]TG-VLDL, we found that LRP1 deficiency specifically prevented hypoxia-induced VLDL-[H-3]CE uptake. Finally, in an in vivo porcine model of infarcted myocardium, ischaemic areas exhibited LRP1 protein up-regulation and intramyocardial CE overaccumulation.Our results demonstrate that hypoxia increases LRP1 expression through HIF-1 and that LRP1 overexpression mediates hypoxia-induced VLDL-CE uptake and accumulation in cardiomyocytes.