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: Chiharu Yokoyama, Takuma Aoyama, Takahiro Ido, Akemi Kakino, Takeru Shiraki, Toshiki Tanaka, Kazuhiko Nishigaki, Aiko Hasegawa, Yoshiko Fujita, Tatsuya Sawamura, Shinya Minatoguchi
• Journal: PloS one (PLoS One) Vol. 11 Issue 5 Pg. e0154994 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27195769 (Publication Type: Journal Article)

Chemical References

• Olr1 protein, mouse
• Reactive Oxygen Species
• Scavenger Receptors, Class E
• Doxorubicin
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cardiomyopathies (chemically induced, metabolism)
• Cell Adhesion
• Doxorubicin (adverse effects)
• Echocardiography
• Fibroblasts (metabolism)
• Fibrosis (metabolism)
• Gene Expression Regulation
• Heart Ventricles (pathology)
• Hemodynamics
• Humans
• Inflammation
• Leukocytes (cytology)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Cardiac (metabolism)
• Reactive Oxygen Species (metabolism)
• Scavenger Receptors, Class E (genetics, physiology)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)