title: The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.
abstract: 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.
authors.affiliation: Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Jeanna C
authors.initials: JC
authors.lastname: Perman
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.forename: Malin
authors.initials: M
authors.lastname: Lindbom
authors.forename: Ulf
authors.initials: U
authors.lastname: Lidberg
authors.forename: Marcus
authors.initials: M
authors.lastname: StÅhlman
authors.forename: Daniel
authors.initials: D
authors.lastname: Hägg
authors.forename: Henrik
authors.initials: H
authors.lastname: Lindskog
authors.forename: Margareta
authors.initials: M
authors.lastname: Scharin Täng
authors.forename: Elmir
authors.initials: E
authors.lastname: Omerovic
authors.forename: Lillemor
authors.initials: L
authors.lastname: Mattsson Hultén
authors.forename: Anders
authors.initials: A
authors.lastname: Jeppsson
authors.forename: Petur
authors.initials: P
authors.lastname: Petursson
authors.forename: Johan
authors.initials: J
authors.lastname: Herlitz
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.forename: Sven-Olof
authors.initials: SO
authors.lastname: Olofsson
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D015996:Survival Rate; D014280:Triglycerides / Q000633:toxicity*
chemical_list: D008055:Lipids; D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor