title: DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes.
abstract: Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes.
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China; Department of Forensic Medicine, Guangdong Medical University, Dongguan 523808, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Dunpeng
authors.initials: D
authors.lastname: Cai
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Chuanxiang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Enping
authors.initials: E
authors.lastname: Huang
authors.affiliation: Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: xieweib@126.com.
authors.forename: Wei-Bing
authors.initials: WB
authors.lastname: Xie
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: hjwang711@yahoo.cn.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D018929:Cell Culture Techniques; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D015870:Gene Expression; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D000697:Central Nervous System Stimulants; C469991:DDIT4 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D008694:Methamphetamine; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Autophagy; Cardiotoxicity; DDIT4 (DNA damage-inducible transcript 4); Methamphetamine