title: Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.
abstract: Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory cells. Endothelial cells, fibroblasts and inflammatory cells treated with DOX showed no elevated LOX-1 expression compared with those treated with vehicle. However, cardiomyocytes treated with DOX showed much more expression of LOX-1 than those treated with vehicle. Immunohistochemistry study also showed that LOX-1 expression was strongly elevated in cardiomyocytes in the heart tissue of mice treated with DOX in vivo. We conclude that LOX-1 in cardiomyocytes plays the most important roles in the pathology of DOX-induced cardiomyopathy. LOX-1 deletion altered the LOX-1-related signaling pathway, which led to improvements in cardiac function, myocardial inflammation, fibrosis and degenerative changes after DOX treatment.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Yokoyama
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.|Cardiovascular Center, Kizawa Memorial Hospital, Minokamo, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.|Cardiovascular Center, Kizawa Memorial Hospital, Minokamo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ido
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.|Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Kakino
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Shiraki
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishigaki
authors.affiliation: Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.|Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism*; D002448:Cell Adhesion; D004317:Doxorubicin / Q000009:adverse effects*; D004452:Echocardiography; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases