Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats.
Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats.
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DOI：
10.1016/j.redox.2022.102523
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发表时间：
2022-12
期刊：
影响因子：
11.4
通讯作者：
Bhuiyan, Md. Shenuarin
中科院分区：
文献类型：
--
作者：
Abdullah, Chowdhury S.;Remex, Naznin Sultana;Aishwarya, Richa;Nitu, Sadia;Kolluru, Gopi K.;Traylor, James;Hartman, Brandon;King, Judy;Bhuiyan, Mohammad Alfrad Nobel;Hall, Nicole;Murnane, Kevin Sean;Goeders, Nicholas E.;Kevil, Christopher G.;Orr, A. Wayne;Bhuiyan, Md. Shenuarin
甲基苯丙胺是一种高度上瘾的精神刺激剂，由于其中枢和外周毒性作用，最近非法使用甲基苯丙胺的情况有所增加，这是一种巨大的卫生保健负担。越来越多的临床研究已经注意到，在人类中使用冰毒与心肌病的发展有关；然而，临床前研究和动物模型剖析冰毒相关心肌病发生的详细分子机制的研究和动物模型很少。本研究利用一种独特的冰毒自我给药的长时间狂欢和崩溃程序来表征与冰毒相关的心肌病所发生的病理改变的后遗症。允许大鼠自我静脉注射冰毒，持续每周96小时，持续8周。停药24小时后进行心功能、组织化学、超微结构和生化实验。自愿给药可导致病理性心脏重构，表现为心肌细胞肥大、心肌细胞紊乱、间质及血管周围纤维化，并伴有心脏收缩功能受损。超微结构检查和天然凝胶电泳显示，冰毒暴露心脏线粒体形态发生改变，线粒体氧化磷酸化(OXPHOS)超复合体(SCs)的稳定性和组装能力降低。氧化还原敏感性分析显示线粒体呼吸复合体活性显著减弱，丙酮酸脱氢酶(PDH)活性代偿性增加，这让人想起代谢重塑。在冰毒暴露的心脏中，观察到自噬通量增加和线粒体抗氧化蛋白水平增加。MitoTEMPO治疗降低了自噬水平，表明线粒体功能障碍参与了冰毒暴露心脏自噬的适应性激活。总之，我们报道了一种使用自愿寻药行为的新的冰毒相关性心肌病模型。我们的研究表明，冰毒自我给药深刻影响线粒体超微结构、OXPHOS SCs组装和氧化还原活性，并伴随PDH活性增加，这可能是观察到的心功能障碍的基础。
The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96 h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24 h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction.
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DOI：
10.3791/53266
发表时间：
2016-01-22
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Batra V;Guerin GF;Goeders NE;Wilden JA
通讯作者：
Wilden JA
影响因子：
--
作者：
ALLARD, MF;SCHONEKESS, BO;LOPASCHUK, GD
通讯作者：
LOPASCHUK, GD
影响因子：
5.4
作者：
Curran, Lara;Nah, Gregory;Marcus, Gregory M.;Tseng, Zian;Crawford, Michael H.;Parikh, Nisha, I
通讯作者：
Parikh, Nisha, I
影响因子：
4.4
作者：
Abdullah CS;Aishwarya R;Alam S;Remex NS;Morshed M;Nitu S;Miriyala S;Panchatcharam M;Hartman B;King J;Alfrad Nobel Bhuiyan M;Traylor J;Kevil CG;Orr AW;Bhuiyan MS
通讯作者：
Bhuiyan MS
影响因子：
5.6
作者：
Bazylianska V;Sharma A;Chauhan H;Schneider B;Moszczynska A
通讯作者：
Moszczynska A