Toll-interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis
Toll-interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis
复制标题
Toll相互作用蛋白通过促进炎症和细胞凋亡导致心肌梗死后的死亡率
DOI：
10.1111/bph.13130
复制
发表时间：
2015-07-01
影响因子：
7.3
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Wan, Nian;Liu, Xiaoxiong;Li, Hongliang
背景和目的Toll相互作用蛋白（Tollip）是一种内源性Toll样受体抑制剂，Toll样受体是一个在包括心肌梗死（MI）在内的多种病理状态中起关键作用的超家族。本实验分别在Tollip基因敲除（KO）小鼠、心脏特异性过表达人Tollip基因的小鼠及其Tollip（+/+）和非转基因对照小鼠中建立了实验性ApproachMI模型。以死亡率、梗死面积和心功能为指标评价Tollip对MI的影响。缺氧诱导的心肌细胞损伤在体外进行了研究，以确认Tollip在心脏damage.Key ResultsTollip表达的作用显着上调在人类缺血性心脏和梗死小鼠心脏。与Tollip（+/+）对照组相比，Tollip-KO小鼠MI诱导的死亡率、梗死面积和心功能障碍降低。Tollip-KO小鼠的缺血性心脏表现出炎性细胞浸润减少和NF-B活化减少。Tollip耗竭还通过下调梗死边缘区促凋亡蛋白水平和上调抗凋亡蛋白表达来减轻心肌细胞凋亡。相反，心肌梗死的影响加剧与心脏特异性Tollip过度表达的小鼠。Tollip在体内加重了MI损伤，并在体外试验中得到证实。Akt信号的抑制与Tollip对MI损伤的有害影响; Akt的激活在很大程度上逆转了Tollip对MI诱导的心肌细胞death.Conclusions和ImplicationsTollip的有害影响促进MI后的炎症和凋亡反应，导致死亡率增加和心功能不全加重。这些结果表明，Tollip可能作为一个新的治疗心肌梗死的治疗靶点。
Background and PurposeToll-interacting protein (Tollip) is an endogenous inhibitor of toll-like receptors, a superfamily that plays a pivotal role in various pathological conditions, including myocardial infarction (MI). However, the exact role of Tollip in MI remains unknown.Experimental ApproachMI models were established in Tollip knockout (KO) mice, mice with cardiac-specific overexpression of human Tollip gene and in their Tollip(+/+) and non-transgenic controls respectively. The effects of Tollip on MI were evaluated by mortality, infarct size and cardiac function. Hypoxia-induced cardiomyocyte damage was investigated in vitro to confirm the role of Tollip in heart damage.Key ResultsTollip expression was dramatically up-regulated in human ischaemic hearts and infarcted mice hearts. MI-induced mortality, infarct size and cardiac dysfunction were decreased in Tollip-KO mice compared with Tollip(+/+) controls. Ischaemic hearts from Tollip-KO mice exhibited decreased inflammatory cell infiltration and reduced NF-B activation. Tollip depletion also alleviated myocardial apoptosis by down-regulating pro-apoptotic protein levels and up-regulating anti-apoptotic protein expressions in infarct border zone. Conversely, MI effects were exacerbated in mice with cardiac-specific Tollip overexpression. This aggravated MI injury by Tollip in vivo was confirmed with in vitro assays. Inhibition of Akt signalling was associated with the detrimental effects of Tollip on MI injury; activation of Akt largely reversed the deleterious effects of Tollip on MI-induced cardiomyocyte death.Conclusions and ImplicationsTollip promotes inflammatory and apoptotic responses after MI, leading to increased mortality and aggravated cardiac dysfunction. These findings suggest that Tollip may serve as a novel therapeutic target for the treatment of MI.