The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

被引:141
作者
Perman, Jeanna C. [1 ,2 ]
Bostrom, Pontus [1 ,2 ]
Lindbom, Malin [1 ,2 ]
Lidberg, Ulf [1 ,2 ]
Stahlman, Marcus [1 ,2 ]
Hagg, Daniel [1 ,2 ]
Lindskog, Henrik [1 ,2 ]
Tang, Margareta Scharin [1 ,2 ]
Omerovic, Elmir [1 ,2 ]
Hulten, Lillemor Mattsson [1 ,2 ]
Jeppsson, Anders [2 ]
Petursson, Petur [2 ]
Herlitz, Johan [2 ]
Olivecrona, Gunilla [3 ]
Strickland, Dudley K. [4 ]
Ekroos, Kim [5 ]
Olofsson, Sven-Olof [1 ,2 ]
Boren, Jan [1 ,2 ]
机构
[1] Sahlgrens Univ Hosp, Wallenberg Lab, Sahlgrenska Ctr Cardiovasc & Metab Res, SE-41345 Gothenburg, Sweden
[2] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden
[3] Umea Univ, Dept Med Biosci Physiol Chem, Umea, Sweden
[4] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA
[5] Zora Biosci, Espoo, Finland
基金
瑞典研究理事会;
关键词
LOW-DENSITY-LIPOPROTEIN; ENDOPLASMIC-RETICULUM STRESS; CYTOSOLIC LIPID DROPLETS; LIQUID-CHROMATOGRAPHY; HIGH-THROUGHPUT; ER STRESS; MASS; CELLS; METABOLISM; CERAMIDE;
D O I
10.1172/JCI43068
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1 alpha through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr(-/-) mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr(-/-) mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.
引用
收藏
页码:2625 / 2640
页数:16
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