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JBC:雷帕霉素可预防糖尿病相关心脏并发症

来源:生物谷 2014-02-23 20:58

2014年2月24日讯 /生物谷BIOON/--根据弗吉尼亚联邦大学一项新的研究证实:使用低剂量以提高器官移植患者生存的药物,可以改善糖尿病动物模型代谢和心脏功能障碍。

由于2型糖尿病患者的数量大量增多,预计在未来20年会增加一倍,研究人员正在努力分析糖尿病和心脏疾病之间的关系,以确定新的药物靶点的分子。糖尿病与心脏发作有关,空腹血糖升高患者心脏发作之后死亡风险增加三倍。

公布在Journal of Biological Chemistry杂志上这项研究中,研究人员报告说,用于提高器官移植患者生存的抗生素雷帕霉素,可以预防动物模型2型糖尿病相关的心脏并发症。

采用尖端的生理,分子和蛋白质组方法,团队仔细审查一个关键信号通路雷帕霉素( mTOR)。它是一种信号转导途径,主要负责调节细胞生长和代谢,并且已被证实牵涉多种人类疾病,包括糖尿病。

雷帕霉素的治疗可改善糖尿病小鼠代谢、显著降低体重,心脏重量,血糖,胰岛素水平和甘油三酯的含量。此外,该药物可以防止糖尿病小鼠的心功能不全,可能机制为通过减少氧化应激和抗氧化剂的改变有助于维持糖尿病心脏收缩力的蛋白质。

2006年,发表在Journal of Molecular and Cellular Cardiology杂志的一项研究中,该研究小组报告雷帕霉素对心脏疾病非糖尿病动物模型的保护作用。根据Das和Kukreja表示,还需要进一步研究,以了解雷帕霉素对糖尿病患者代谢和心脏功能益处的分子机制。(生物谷Bioon.com)

doi:10.1074/jbc.M113.521062
Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Anindita Das,et al.

Elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes, with increased morbidity and mortality, mainly because of cardiovascular complications. Because mTOR inhibition with rapamycin protects against ischemia/reperfusion injury, we hypothesized that rapamycin would prevent cardiac dysfunction associated with type 2 diabetes (T2D). We also investigated the possible mechanisms and novel protein targets involved in rapamycin-induced preservation of cardiac function in T2D mice. Adult male leptin receptor null, homozygous db/db, or wild type mice were treated daily for 28 days with vehicle (5% DMSO) or rapamycin (0.25 mg/kg, intraperitoneally). Cardiac function was monitored by echocardiography, and protein targets were identified by proteomics analysis. Rapamycin treatment significantly reduced body weight, heart weight, plasma glucose, triglyceride, and insulin levels in db/db mice. Fractional shortening was improved by rapamycin treatment in db/db mice. Oxidative stress as measured by glutathione levels and lipid peroxidation was significantly reduced in rapamycin-treated db/db hearts. Rapamycin blocked the enhanced phosphorylation of mTOR and S6, but not AKT in db/db hearts. Proteomic (by two-dimensional gel and mass spectrometry) and Western blot analyses identified significant changes in several cytoskeletal/contractile proteins (myosin light chain MLY2, myosin heavy chain 6, myosin-binding protein C), glucose metabolism proteins (pyruvate dehydrogenase E1, PYGB, Pgm2), and antioxidant proteins (peroxiredoxin 5, ferritin heavy chain 1) following rapamycin treatment in db/db heart. These results show that chronic rapamycin treatment prevents cardiac dysfunction in T2D mice, possibly through attenuation of oxidative stress and alteration of antioxidants and contractile as well as glucose metabolic protein expression.

 

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