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MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats.
https://asahi-u.repo.nii.ac.jp/records/3232
https://asahi-u.repo.nii.ac.jp/records/3232011d794d-12e9-4270-b90b-57d03c18706f
| Item type | 朝日大学 教育・研究業績(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2015-02-25 | |||||
| タイトル | ||||||
| タイトル | MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats. | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_1843 | |||||
| 資源タイプ | other | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 業績分類 | ||||||
| 値 | 学術雑誌論文 | |||||
| 教員氏名 |
竹村, 元三
× 竹村, 元三 |
|||||
| 発行、発表雑誌等、又は発表学会等の名称 | ||||||
| 値 | Biochim Biophys Acta. | |||||
| 巻 | ||||||
| 値 | 1842 | |||||
| 号 | ||||||
| 値 | 5 | |||||
| 掲載ページ | ||||||
| 値 | 691-700 | |||||
| 単著、共著の別 | ||||||
| 値 | 共著 | |||||
| 発行又は発表の年月 | ||||||
| 日付 | 2014-05 | |||||
| PubMed番号 | ||||||
| 値 | 24491919 | |||||
| 概要 | ||||||
| 値 | The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart. | |||||
