Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4873018?pdf=render |
| _version_ | 1798044198849478656 |
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| author | Chiharu Yokoyama Takuma Aoyama Takahiro Ido Akemi Kakino Takeru Shiraki Toshiki Tanaka Kazuhiko Nishigaki Aiko Hasegawa Yoshiko Fujita Tatsuya Sawamura Shinya Minatoguchi |
| author_facet | Chiharu Yokoyama Takuma Aoyama Takahiro Ido Akemi Kakino Takeru Shiraki Toshiki Tanaka Kazuhiko Nishigaki Aiko Hasegawa Yoshiko Fujita Tatsuya Sawamura Shinya Minatoguchi |
| author_sort | Chiharu Yokoyama |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T22:59:43Z |
| format | Article |
| id | doaj.art-a9a8e38f4f1e44b7b86bc56099c7a5b3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-11T22:59:43Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-a9a8e38f4f1e44b7b86bc56099c7a5b32022-12-22T03:58:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015499410.1371/journal.pone.0154994Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.Chiharu YokoyamaTakuma AoyamaTakahiro IdoAkemi KakinoTakeru ShirakiToshiki TanakaKazuhiko NishigakiAiko HasegawaYoshiko FujitaTatsuya SawamuraShinya MinatoguchiOxidative 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.http://europepmc.org/articles/PMC4873018?pdf=render |
| spellingShingle | Chiharu Yokoyama Takuma Aoyama Takahiro Ido Akemi Kakino Takeru Shiraki Toshiki Tanaka Kazuhiko Nishigaki Aiko Hasegawa Yoshiko Fujita Tatsuya Sawamura Shinya Minatoguchi Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. PLoS ONE |
| title | Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. |
| title_full | Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. |
| title_fullStr | Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. |
| title_full_unstemmed | Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. |
| title_short | Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin. |
| title_sort | deletion of lox 1 protects against heart failure induced by doxorubicin |
| url | http://europepmc.org/articles/PMC4873018?pdf=render |
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