Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia.
Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia.
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DOI：
10.1111/j.1582-4934.2009.00798.x
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Zhao P;Wang J;He L;Ma H;Zhang X;Zhu X;Dolence EK;Ren J;Li J
Toll样受体4（TLR 4）是对革兰氏阴性病原体的脂多糖的先天性免疫应答中的近端信号受体，在心脏中表达。越来越多的证据已经巩固了TLR 4在心功能不全的发病机制中起重要作用的观点。然而，TLR 4负责缺血诱导的心功能不全的分子机制仍不清楚。为了解决TLR 4缺陷心脏保护对抗缺血性损伤的信号传导机制，在野生型（WT）C3 H/HeN和TLR 4突变的C3 H/HeJ小鼠中通过闭塞左前降支冠状动脉诱导体内局部缺血。结果表明，与C3 H/HeN心脏相比，C3 H/HeJ心脏中p38丝裂原活化蛋白激酶和JNK信号通路的缺血激活减弱，而与C3 H/HeN心脏相比，C3 H/HeJ心脏中ERK和AMP活化蛋白激酶（AMPK）信号通路在缺血期间增强。有趣的是，缺血刺激的内质网应激在C3 H/HeN中比在C3 H/HeJ中更高，这通过Grp 78/BiP、Gadd 153/CHOP和IRE-1α的上调来证明。心肌梗死、caspase-3活性和末端脱氧核苷酸转移酶（dUTP）缺口末端标记（TUNEL）染色结果表明，C3 H/HeN心肌缺血时损伤程度明显高于C3 H/HeJ心肌。此外，与来自C3 H/HeN心脏的心肌细胞相比，来自C3 H/HeJ心脏的分离的心肌细胞显示出对缺氧诱导的收缩功能障碍的抵抗，这与AMPK和ERK信号转导的更大的缺氧激活、C3 H/HeJ中比C3 H/HeN心肌细胞更好的细胞内Ca 2+处理相关。这些结果提示TLR 4信号通路缺陷对缺血性心脏损伤的保护作用可能是通过调节AMPK和ERK信号通路来实现的。
Toll-like receptor 4 (TLR4), a proximal signalling receptor in innate immune responses to lipopolysaccharide of gram-negative pathogens, is expressed in the heart. Accumulating evidence have consolidated the notion that TLR4 plays an essential role in the pathogenesis of cardiac dysfunction. However, the molecular mechanisms of TLR4 responsible for ischemia-induced cardiac dysfunction remain unclear. To address the signalling mechanisms of TLR4-deficiency cardioprotection against ischemic injury, in vivo regional ischemia was induced by occlusion of the left anterior descending coronary artery in wild-type (WT) C3H/HeN and TLR4-mutated C3H/HeJ mice. The results demonstrated that blunted ischemic activation of p38 mitogen-activated protein kinase and JNK signalling occurred in C3H/HeJ hearts versus C3H/HeN hearts, while ERK and AMP-activated protein kinase (AMPK) signalling pathways were augmented during ischemia in C3H/HeJ hearts versus C3H/HeN hearts. Intriguingly, ischemia-stimulated endoplasmic reticulum stress was higher in C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE-1α. Myocardial infarct, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining demonstrated that C3H/HeN hearts suffered more damage than those of C3H/HeJ hearts during ischemia. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to hypoxia-induced contractile dysfunction compared to those from C3H/HeN hearts, which are associated with greater hypoxic activation of AMPK and ERK signalling, better intracellular Ca2+ handling in C3H/HeJ versus C3H/HeN cardiomyocytes. These findings suggest that the cardioprotective effects against ischemic injury of hearts with deficiency in TLR4 signalling may be mediated through modulating AMPK and ERK signalling pathway during ischemia.
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