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 2625-40

Ämneskategorier

MEDICIN OCH HÄLSOVETENSKAP

DOI

10.1172/JCI43068

PubMed

21670500