論文 - 詳細
| RRC ID | 18540 |
|---|---|
| 著者 | Kawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, Ogino A, Tsujimoto A, Goto K, Maruyama R, Kawasaki M, Mikami A, Fujiwara T, Fujiwara H, Minatoguchi S. |
| タイトル | Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. |
| ジャーナル | Cardiovasc Res |
| Abstract |
AIMS:Active autophagy has recently been reported in doxorubicin-induced cardiotoxicity; here we investigated its pathophysiological role. METHODS AND RESULTS:Acute cardiotoxicity was induced in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice by administering two intraperitoneal injections of 10 mg/kg doxorubicin with a 3 day interval. A starvation group was deprived of food for 48 h before each injection to induce autophagy in advance. Doxorubicin treatment caused left ventricular dilatation and dysfunction within 6 days. Cardiomyocyte autophagy appeared to be activated in the doxorubicin group, based on LC3, p62, and cathepsin D expression, while it seemed somewhat diminished by starvation prior to doxorubicin treatment. Unexpectedly, however, myocardial ATP levels were reduced in the doxorubicin group, and this reduction was prevented by earlier starvation. Electron microscopy revealed that the autophagic process was indeed initiated in the doxorubicin group, as shown by the increased lysosomes, but was not completed, i.e. autophagolysosome formation was rare. Starvation prior to doxorubicin treatment partly restored autophagosome formation towards control levels. Autophagic flux assays in both in vivo and in vitro models confirmed that doxorubicin impairs completion of the autophagic process in cardiomyocytes. The activities of both AMP-activated protein kinase and the autophagy-initiating kinase unc-51-like kinase 1 (ULK1) were found to be decreased by doxorubicin, and these were restored by prior starvation. CONCLUSION:Prior starvation mitigates acute doxorubicin cardiotoxicity; the underlying mechanism may be, at least in part, restoration and further augmentation of myocardial autophagy, which is impaired by doxorubicin, probably through inactivation of AMP-activated protein kinase and ULK1. |
| 巻・号 | 96(3) |
| ページ | 456-65 |
| 公開日 | 2012-12-1 |
| DOI | 10.1093/cvr/cvs282 |
| PII | cvs282 |
| PMID | 22952253 |
| MeSH | AMP-Activated Protein Kinases / metabolism Adenosine Triphosphate / metabolism Animals Antibiotics, Antineoplastic* Autophagy / drug effects* Autophagy-Related Protein-1 Homolog Cathepsin D / metabolism Cells, Cultured Doxorubicin* Energy Metabolism Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Heart Failure / chemically induced Heart Failure / metabolism Heart Failure / pathology Heart Failure / physiopathology Heart Failure / prevention & control* Hypertrophy, Left Ventricular / chemically induced Hypertrophy, Left Ventricular / metabolism Hypertrophy, Left Ventricular / pathology Hypertrophy, Left Ventricular / physiopathology Hypertrophy, Left Ventricular / prevention & control* Mice Mice, Transgenic Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Myocytes, Cardiac / metabolism Myocytes, Cardiac / pathology* Protein Serine-Threonine Kinases / metabolism Rats Starvation / complications* Starvation / metabolism Stroke Volume Time Factors Ventricular Dysfunction, Left / chemically induced Ventricular Dysfunction, Left / metabolism Ventricular Dysfunction, Left / pathology Ventricular Dysfunction, Left / physiopathology Ventricular Dysfunction, Left / prevention & control* Ventricular Function, Left Ventricular Pressure |
| IF | 8.168 |
| 引用数 | 74 |
| WOS 分野 | CARDIAC & CARDIOVASCULAR SYSTEMS |
| リソース情報 | |
| 実験動物マウス | RBRC00806 |