Nature2014-06-17 2:46 PM

支架内再狭窄的可能药物治疗 Dichloroacetate prevents restenosis in preclinical animal models of vessel injury

论文摘要 

支架内再狭窄(血管或心脏瓣膜变窄的现象)是用心脏支架(金属或塑料管子)来治疗冠状动脉病所经常发生的一种并发症。这种状况以平滑肌细胞增生以及肌内膜或最内部血管壁的细胞增生为特征。Sonja Schrepfer及同事对这些增生细胞在形成过程中的代谢特点进行了表征,发现存在瞬态线粒体重新编程和代谢被改变。他们发现,药物“二氯乙酸盐”(已知能够抑制肿瘤生长) 在若干临床前模型中能够防止这些代谢改变中的一些,减少肌内膜增生——至少部分是通过抑制“丙酮酸脱氢酶激酶-2”来发挥这种作用的。

Abstract 

Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States1. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation2, 3 and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

Nature

Nature Magazine

0 Following 27 Fans 0 Projects 626 Articles

SIMILAR ARTICLES

Meristems encompass stem/progenitor cells that sustain postembryonic growth of all plant organs. How meristems are activated and sustained by nutrient

Read More

Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of P

Read More

Abstract The effect of anthropogenic aerosols on cloud droplet concentrations and radiative properties is the source of one of the largest uncertainti

Read More

Abstract Ecological and societal disruptions by modern climate change are critically determined by the time frame over which climates shift beyond his

Read More

Abstract Evidence from Greenland ice cores shows that year-to-year temperature variability was probably higher in some past cold periods, but there is

Read More

Abstract The land and ocean act as a sink for fossil-fuel emissions, thereby slowing the rise of atmospheric carbon dioxide concentrations1. Although t

Read More

论文摘要 人们已经非常清楚生物多样性对初级生产力等生态系统功能有一个积极影响,但它对植物凋落物的多样性和分解植物凋落物的生物的多样性的影响却不是很清楚。Stephan H?ttenschwiler及同事对从亚北极到热带、包括水生生态系统和陆地生态系统在内的五个地点所进行的并行操纵实验中的凋落物多样性进

Read More

论文摘要 FANTOM5 (即“哺乳动物基因组-5的功能注解”) 是一个大型国际合作项目的第5大阶段,其目标是分析定义每个人类细胞类型的转录调控网络。本期Nature上的两篇Articles论文发表了该项目的一些最新结果。第一篇论文利用FANTOM5项目组的组织和原代细胞样本来定义整个人体中活性的、在

Read More

论文摘要 有证据表明,血管 (尤其是它们的内皮细胞) 控制器官的生长、平衡和再生。在本期Nature上发表的两篇论文中,Ralf Adams及同事证明,骨头血管含有专门支持骨成熟和再生的内皮细胞。Anjali Kusumbe等人在小鼠骨骼系统内识别出一个在介导骨生长中起关键作用的毛细血管亚型。这些血管

Read More

论文摘要 CD4 T细胞(携带能够识别被病毒感染的细胞表面上的CD4抗原的受体的辅助T细胞)的丧失是艾滋病发病的根源。在这项研究中,Warner Greene等人识别出静止的淋巴CD4 T细胞在HIV感染过程中被耗尽的机制。利用保持了天然淋巴环境的人淋巴组织的体外培养,本文作者发现,失败的病毒复制触发

Read More