细胞生物学
线粒体通透性转换孔
促炎细胞因子
氧化应激
信号转导
ASK1
程序性细胞死亡
细胞凋亡
生物
激酶
医学
炎症
内科学
蛋白激酶A
生物化学
丝裂原活化蛋白激酶激酶
作者
Masatsugu Hori,K. Nishida
出处
期刊:Cardiovascular Research
[Oxford University Press]
日期:2008-10-29
卷期号:81 (3): 457-464
被引量:462
摘要
In acute myocardial infarction (MI), reactive oxygen species (ROS) are generated in the ischaemic myocardium especially after reperfusion. ROS directly injure the cell membrane and cause cell death. However, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and -6, in the ischaemic region and surrounding myocardium as a host reaction. Inflammatory cytokines also regulate cell survival and cell death in the chain reaction with ROS. Both ROS and inflammatory cytokines are cardiodepressant mainly due to impairment of intracellular Ca2+ homeostasis. Inflammatory cytokines stimulate apoptosis through a TNF-α receptor/caspase pathway, whereas Ca2+ overload induced by extensive ROS generation causes necrosis through enhanced permeability of the mitochondrial membrane (mitochondrial permeability transition). Apoptosis signal-regulating kinase-1 (ASK1) is an ROS-sensitive, mitogen-activated protein kinase kinase kinase that is activated by many stress signals and can activate nuclear factor κB and other transcription factors. ASK1-deficient mice demonstrate that the ROS/ASK1 pathway is involved in necrotic as well as apoptotic cell death, indicating that ASK1 may be a therapeutic target to reduce left ventricular (LV) remodelling after MI. ROS and inflammatory cytokines activate matrix metalloproteinases which degrade extracellular matrix, causing a slippage of myofibrils and hence LV dilatation. Consequently, collagen deposition is increased and tissue repair is enhanced with myocardial fibrosis and angiogenesis. Since the extent of LV remodelling is a major predictor of prognosis of the patients with MI, the therapeutic approach to attenuating LV remodelling is critically important.
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