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Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.
PLoS One. 2016; 11(5):e0154994.Plos

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-1β) 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+Show Affiliations

Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan. Cardiovascular Center, Kizawa Memorial Hospital, Minokamo, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan. Cardiovascular Center, Kizawa Memorial Hospital, Minokamo, Japan.Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27195769

Citation

Yokoyama, Chiharu, et al. "Deletion of LOX-1 Protects Against Heart Failure Induced By Doxorubicin." PloS One, vol. 11, no. 5, 2016, pp. e0154994.
Yokoyama C, Aoyama T, Ido T, et al. Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. PLoS One. 2016;11(5):e0154994.
Yokoyama, C., Aoyama, T., Ido, T., Kakino, A., Shiraki, T., Tanaka, T., Nishigaki, K., Hasegawa, A., Fujita, Y., Sawamura, T., & Minatoguchi, S. (2016). Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. PloS One, 11(5), e0154994. https://doi.org/10.1371/journal.pone.0154994
Yokoyama C, et al. Deletion of LOX-1 Protects Against Heart Failure Induced By Doxorubicin. PLoS One. 2016;11(5):e0154994. PubMed PMID: 27195769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. AU - Yokoyama,Chiharu, AU - Aoyama,Takuma, AU - Ido,Takahiro, AU - Kakino,Akemi, AU - Shiraki,Takeru, AU - Tanaka,Toshiki, AU - Nishigaki,Kazuhiko, AU - Hasegawa,Aiko, AU - Fujita,Yoshiko, AU - Sawamura,Tatsuya, AU - Minatoguchi,Shinya, Y1 - 2016/05/19/ PY - 2015/07/02/received PY - 2016/04/22/accepted PY - 2016/5/20/entrez PY - 2016/5/20/pubmed PY - 2017/7/14/medline SP - e0154994 EP - e0154994 JF - PloS one JO - PLoS One VL - 11 IS - 5 N2 - 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-1β) 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/27195769/Deletion_of_LOX_1_Protects_against_Heart_Failure_Induced_by_Doxorubicin_ L2 - https://dx.plos.org/10.1371/journal.pone.0154994 DB - PRIME DP - Unbound Medicine ER -