通过阿尔多减少酶介导的p53酸化导致线粒体功能障碍和糖尿病血小板损伤
Wai Ho Tang1, Jeremiah Stitham, Yu Jin
1Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (W.H.T., J.S., Y.J., R.L., S.H.L., J.D., G.A., S.G., K.M., J.H.) and Section of Endocrinology and Metabolism, Department of Internal Medicine (G.S.), Yale University School of Medicine, New Haven, CT.
Circulation
|January 30, 2014
概括
糖尿病的高血糖症会通过阿尔多斯减少酶和p53引起血小板线粒体功能障碍,导致过活性或亡,增加血栓形成的风险.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 血液学 血液学 血液学
背景情况:
- 血小板异常在糖尿病中很常见.
- 线粒体对血小板功能至关重要,在糖尿病中受损.
- 糖尿病中高血糖引起的血小板线粒体功能障碍的特定分子机制尚不清楚.
研究的目的:
- 为了阐明糖尿病中血小板中高血糖引起的线粒体功能障碍的分子途径.
- 为了研究阿尔多减少酶,活性氧物种和p53在这个过程中的作用.
- 为了区分线粒体损伤对血小板激活和亡的结果.
主要方法:
- 利用了人类和人性化的小鼠模型.
- 评估过高血糖引起的阿尔多减少酶激活和反应性氧物种 (ROS) 生产.
- 分析了p53酸化 (Ser15),线粒体完整性和血小板亡标志物 (细胞染色体c释放,卡斯帕酶3激活,酸暴露).
主要成果:
- 过高血糖会激活阿尔多减少酶并增加ROS,导致p53酸化和线粒体功能障碍,损伤和破裂.
- 严重的线粒体损伤导致血小板亡 (膜潜力的损失,细胞染色体c释放,酶3激活,酸暴露).
- 血小板过活化和亡是不同的结果,取决于高血糖症的严重程度和线粒体损伤,两者都会导致血栓形成的增加.
结论:
- 阿尔多斯减少酶激活p53调解糖尿病相关的线粒体功能障碍和血小板损伤.
- 线粒体损伤的程度决定了血小板是否变得过度活跃 (轻度损伤) 或发生亡 (严重损伤).
- 这些途径代表了管理糖尿病中血栓性并发症的潜在治疗点.
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