Cardiac Ischemic Preconditioning Promotes MG53 Secretion Through H2O2-Activated Protein Kinase C-δ Signaling
Cardiac Ischemic Preconditioning Promotes MG53 Secretion Through H2O2-Activated Protein Kinase C-δ Signaling
复制标题
心脏缺血预处理通过 H(2)O(2) 激活的蛋白激酶 C-δ 信号传导促进 MG53 分泌。
DOI：
10.1161/circulationaha.119.044998
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发表时间：
2020-09-15
期刊：
影响因子：
37.8
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
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作者：
Shan, Dan;Guo, Sile;Xiao, Rui-Ping
背景：缺血性心脏病是世界范围内发病率和死亡率的主要原因。缺血预适应(IPC)是对抗心肌缺血/再灌注损伤最有效的内在保护机制。以往的研究表明，多功能TRIM家族蛋白MG53(mitsugumin 53；又称TRIM72)不仅在IPC介导的心肌缺血/再灌注损伤保护中发挥重要作用，而且还可以改善机械损伤。除了细胞内的作用外，MG53作为一种肌肉因子/心脏因子，可以从心脏和骨骼肌中分泌出来，以响应代谢应激。然而，目前尚不清楚IPC介导的心肌保护是否与MG53分泌有因果关系，如果是，其潜在机制是什么。方法：应用蛋白质组学分析，结合遗传学和药理学方法，我们在活体啮齿动物、分离的灌流心脏和培养的新生大鼠心肌细胞上检测了IPC对MG53分泌的影响，并探讨了其可能的机制。此外，利用重组的MG53蛋白，我们研究了分泌的MG53在缺血预适应和缺血/再灌注损伤中的潜在生物学功能。结果：我们发现IPC在啮齿动物体内、灌流心脏和培养的心肌细胞中触发了旺盛的MG53分泌，而不会导致细胞膜渗漏。机制上，IPC通过H_2O_2诱导蛋白激酶C-Delta的激活促进MG53的分泌。具体地说，IPC诱导的心肌MG53分泌是由过氧化氢触发的Y311蛋白激酶C-Delta的磷酸化所介导的，这是促进MG53分泌所必需的，也是充分的。在功能上，重组MG53蛋白模拟升高的循环MG53不仅恢复了MG53缺陷小鼠的IPC功能，而且即使在没有IPC的情况下，也能保护啮齿动物的心脏免受缺血/再灌注损伤。此外，H(2)O(2)引起的氧化应激增加了MG53的分泌，而MG53被敲除后加剧了过氧化氢诱导的人胚胎干细胞来源的心肌细胞的细胞损伤，尽管MG53在人心脏中的基础表达相对较低。结论：IPC和氧化应激可通过依赖H_2O_2-蛋白激酶-C-增量的机制刺激心脏分泌MG53，细胞外MG53可能参与IPC对心肌缺血/再灌注损伤的保护作用。
Background: Ischemic heart disease is the leading cause of morbidity and mortality worldwide. Ischemic preconditioning (IPC) is the most powerful intrinsic protection against cardiac ischemia/reperfusion injury. Previous studies have shown that a multifunctional TRIM family protein, MG53 (mitsugumin 53; also called TRIM72), not only plays an essential role in IPC-mediated cardioprotection against ischemia/reperfusion injury but also ameliorates mechanical damage. In addition to its intracellular actions, as a myokine/cardiokine, MG53 can be secreted from the heart and skeletal muscle in response to metabolic stress. However, it is unknown whether IPC-mediated cardioprotection is causally related to MG53 secretion and, if so, what the underlying mechanism is. Methods: Using proteomic analysis in conjunction with genetic and pharmacological approaches, we examined MG53 secretion in response to IPC and explored the underlying mechanism using rodents in in vivo, isolated perfused hearts, and cultured neonatal rat ventricular cardiomyocytes. Moreover, using recombinant MG53 proteins, we investigated the potential biological function of secreted MG53 in the context of IPC and ischemia/reperfusion injury. Results: We found that IPC triggered robust MG53 secretion in rodents in vivo, perfused hearts, and cultured cardiac myocytes without causing cell membrane leakage. Mechanistically, IPC promoted MG53 secretion through H2O2-evoked activation of protein kinase-C-delta. Specifically, IPC-induced myocardial MG53 secretion was mediated by H2O2-triggered phosphorylation of protein kinase-C-delta at Y311, which is necessary and sufficient to facilitate MG53 secretion. Functionally, systemic delivery of recombinant MG53 proteins to mimic elevated circulating MG53 not only restored IPC function in MG53-deficient mice but also protected rodent hearts from ischemia/reperfusion injury even in the absence of IPC. Moreover, oxidative stress by H(2)O(2)augmented MG53 secretion, and MG53 knockdown exacerbated H2O2-induced cell injury in human embryonic stem cell-derived cardiomyocytes, despite relatively low basal expression of MG53 in human heart. Conclusions: We conclude that IPC and oxidative stress can trigger MG53 secretion from the heart via an H2O2-protein kinase-C-delta-dependent mechanism and that extracellular MG53 can participate in IPC protection against cardiac ischemia/reperfusion injury.