HSPA12B Attenuated Acute Myocardial Ischemia/reperfusion Injury via Maintaining Endothelial Integrity in a PI3K/Akt/mTOR-dependent Mechanism.
HSPA12B Attenuated Acute Myocardial Ischemia/reperfusion Injury via Maintaining Endothelial Integrity in a PI3K/Akt/mTOR-dependent Mechanism.
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HSPA12B 通过维持 PI3K/Akt/mTOR 依赖性机制中的内皮完整性减轻急性心肌缺血/再灌注损伤
DOI：
10.1038/srep33636
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发表时间：
2016-09-20
影响因子：
4.6
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Kong Q;Dai L;Wang Y;Zhang X;Li C;Jiang S;Li Y;Ding Z;Liu L
内皮损伤是心肌缺血/再灌注（I/R）损伤的关键介质。 HSPA12B 是一种内皮细胞特异性表达的热休克蛋白。然而，HSPA12B 在急性心肌缺血再灌注损伤中的作用尚不清楚。在此，我们报道心肌I/R上调心室组织中的HSPA12B表达，并且与野生型同窝小鼠相比，转基因小鼠（Tg）中HSPA12B的内皮过度表达限制了梗死面积，减轻了心功能障碍并提高了心肌细胞存活率。这些改善伴随着心肌无复流现象的减少、微血管渗漏的减少以及内皮紧密连接的更好维持。与野生型（WT）同窝小鼠相比，Tg 心脏中 I/R 诱发的中性粒细胞浸润也受到抑制。此外，Tg 心脏在 I/R 攻击后表现出 PI3K/Akt//mTOR 信号传导增强的激活。然而，PI3K 的药理学抑制作用消除了 HSPA12B 诱导的针对心肌 I/R 损伤的心脏保护作用。数据首次证明内皮 HSPA12B 可以保护心脏免受心肌 I/R 损伤。 HSPA12B 的这种心脏保护作用至少部分是通过改善 PI3K/Akt/mTOR 依赖性机制中的内皮完整性来介导的。我们的研究表明，靶向内皮 HSPA12B 可能是治疗心肌缺血再灌注损伤患者的另一种方法。
Endothelial damage is a critical mediator of myocardial ischemia/reperfusion (I/R) injury. HSPA12B is an endothelial-cell-specifically expressed heat shock protein. However, the roles of HSPA12B in acute myocardial I/R injury is unknown. Here we reported that myocardial I/R upregulated HSPA12B expression in ventricular tissues, and endothelial overexpression of HSPA12B in transgenic mice (Tg) limited infarct size, attenuated cardiac dysfunction and improved cardiomyocyte survival compared with their wild type littermates. These improvements were accompanied with the diminished myocardial no-reflow phenomenon, decreased microvascular leakage, and better maintained endothelial tight junctions. The I/R-evoked neutrophil infiltration was also suppressed in Tg hearts compared with its wild type (WT) littermates. Moreover, Tg hearts exhibited the enhanced activation of PI3K/Akt//mTOR signaling following I/R challenge. However, pharmacological inhibition of PI3K abolished the HSPA12B-induced cardioprotection against myocardial I/R injury. The data demonstrate for the first time that the endothelial HSPA12B protected hearts against myocardial I/R injury. This cardioprotective action of HSPA12B was mediated, at least in part, by improving endothelial integrity in a PI3K/Akt/mTOR-dependent mechanism. Our study suggests that targeting endothelial HSPA12B could be an alternative approach for the management of patients with myocardial I/R injury.
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