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Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction
Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that prote...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Japan Atherosclerosis Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800390/ https://www.ncbi.nlm.nih.gov/pubmed/30867376 http://dx.doi.org/10.5551/jat.48405 |
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author | Liu, Jingyi Nishida, Makoto Inui, Hiroyasu Chang, Jiuyang Zhu, Yinghong Kanno, Kotaro Matsuda, Hibiki Sairyo, Masami Okada, Takeshi Nakaoka, Hajime Ohama, Tohru Masuda, Daisaku Koseki, Masahiro Yamashita, Shizuya Sakata, Yasushi |
author_facet | Liu, Jingyi Nishida, Makoto Inui, Hiroyasu Chang, Jiuyang Zhu, Yinghong Kanno, Kotaro Matsuda, Hibiki Sairyo, Masami Okada, Takeshi Nakaoka, Hajime Ohama, Tohru Masuda, Daisaku Koseki, Masahiro Yamashita, Shizuya Sakata, Yasushi |
author_sort | Liu, Jingyi |
collection | PubMed |
description | Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling. Methods: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61(h/h) mice (Hypo E mice) that developed MI by high-fat diet loading. Results: Hypo E mice were fed rivaroxaban-containing (n = 49) or control chow diets (n = 126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p = 0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes. In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts. Conclusions: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway. |
format | Online Article Text |
id | pubmed-6800390 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Japan Atherosclerosis Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-68003902019-10-25 Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction Liu, Jingyi Nishida, Makoto Inui, Hiroyasu Chang, Jiuyang Zhu, Yinghong Kanno, Kotaro Matsuda, Hibiki Sairyo, Masami Okada, Takeshi Nakaoka, Hajime Ohama, Tohru Masuda, Daisaku Koseki, Masahiro Yamashita, Shizuya Sakata, Yasushi J Atheroscler Thromb Original Article Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling. Methods: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61(h/h) mice (Hypo E mice) that developed MI by high-fat diet loading. Results: Hypo E mice were fed rivaroxaban-containing (n = 49) or control chow diets (n = 126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p = 0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes. In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts. Conclusions: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway. Japan Atherosclerosis Society 2019-10-01 /pmc/articles/PMC6800390/ /pubmed/30867376 http://dx.doi.org/10.5551/jat.48405 Text en 2019 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Original Article Liu, Jingyi Nishida, Makoto Inui, Hiroyasu Chang, Jiuyang Zhu, Yinghong Kanno, Kotaro Matsuda, Hibiki Sairyo, Masami Okada, Takeshi Nakaoka, Hajime Ohama, Tohru Masuda, Daisaku Koseki, Masahiro Yamashita, Shizuya Sakata, Yasushi Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title | Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title_full | Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title_fullStr | Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title_full_unstemmed | Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title_short | Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction |
title_sort | rivaroxaban suppresses the progression of ischemic cardiomyopathy in a murine model of diet-induced myocardial infarction |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800390/ https://www.ncbi.nlm.nih.gov/pubmed/30867376 http://dx.doi.org/10.5551/jat.48405 |
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