MPTP公司
线粒体通透性转换孔
心肌保护
再灌注损伤
车站3
缺血
STAT蛋白
肿瘤坏死因子α
药理学
医学
激活剂(遗传学)
化学
信号转导
内科学
细胞凋亡
程序性细胞死亡
生物化学
受体
多巴胺能
多巴胺
作者
Miguel A. Frias,Sarah Pedretti,Damian Hacking,Sarin Somers,Lydia Lacerda,Lionel H. Opie,Richard W. James,Sandrine Lecour
标识
DOI:10.1016/j.atherosclerosis.2013.02.003
摘要
Abstract
Objective
High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening. Methods and results
Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice. Conclusion
Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.
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