The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.
Artikel i vetenskaplig tidskrift, 2011
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-1α 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.
Survival Rate
LDL
genetics
cytology
Stress
Apoptosis
Knockout
Myocardial Infarction
Lipids
pathology
Myocardial Ischemia
Endoplasmic Reticulum
Myocardium
Receptors
metabolism
physiopathology
chemistry
physiology
Mice
Lipid Metabolism
mortality
Humans
physiopathology
toxicity
Physiological
Mice
Cell Line
metabolism
pathology
Triglycerides
Animals
pathology
metabolism
Inbred C57BL
Mice
mortality
Författare
Jeanna Perman
Göteborgs universitet
Pontus Boström
Göteborgs universitet
Malin Lindbom
Göteborgs universitet
Ulf Lidberg
Göteborgs universitet
Marcus Ståhlman
Göteborgs universitet
Daniel Hägg
Göteborgs universitet
Henrik Lindskog
Göteborgs universitet
Margareta Scharin Täng
Göteborgs universitet
Elmir Omerovic
Göteborgs universitet
Lillemor Mattsson Hultén
Göteborgs universitet
Anders Jeppsson
Göteborgs universitet
Petur Petursson
Göteborgs universitet
Johan Herlitz
Göteborgs universitet
Gunilla Olivecrona
Dudley K Strickland
Kim Ekroos
Sven-Olof Olofsson
Göteborgs universitet
Jan Borén
Göteborgs universitet
The Journal of clinical investigation
1558-8238 (ISSN)
Vol. 121 7 2625-40Ämneskategorier
MEDICIN OCH HÄLSOVETENSKAP
DOI
10.1172/JCI43068
PubMed
21670500