Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice.
Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice.
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DOI：
10.1016/j.yjmcc.2020.03.002
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发表时间：
2020-03
影响因子：
5
通讯作者：
W. Xing;Yanzhen Tan;Kaifeng Li;P. Tian;Fei Tian;Haifeng Zhang
中科院分区：
文献类型：
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作者：
W. Xing;Yanzhen Tan;Kaifeng Li;P. Tian;Fei Tian;Haifeng Zhang
2型糖尿病（T2 DM）患者更易发生急性心肌缺血/再灌注（MI/R）损伤。然而，这一机制在很大程度上仍然难以捉摸。临床观察表明，血浆中高水平的肝细胞因子胎球蛋白B（FetB）与糖尿病和冠状动脉疾病显著相关。本研究旨在确定主要来源于肝脏的FetB是否加重MI/R诱导的损伤以及T2 DM的潜在机制。采用高脂饲料和链脲佐菌素诱导T2 DM小鼠模型，MI 30 min后再灌注。糖尿病引起肝FetB表达增加和心肌损伤更大，这可以通过MI/R后细胞凋亡和心肌酶释放增加来证明。在T2 DM心脏中，胰岛素诱导的胰岛素受体底物1 Tyr 608位点和Akt Ser 473位点的磷酸化和葡萄糖转运蛋白4膜转位显著减少。免疫沉淀法检测FetB与胰岛素受体β亚基（IRβ）的相互作用。更重要的是，FetB敲低通过AAV 9减轻MI/R损伤并改善T2 DM小鼠中心脏胰岛素诱导的信号传导。相反，正常小鼠中FetB的上调导致MI/R损伤加重和胰岛素介导的信号传导受损。在培养的新生小鼠心肌细胞中，孵育FetB显着降低IR和胰岛素诱导的葡萄糖摄取的酪氨酸激酶活性，并增加缺氧/复氧诱导的凋亡。此外，FoxO 1敲低siRNA抑制FetB的表达在肝细胞与棕榈酸处理。总之，糖尿病肝脏中FetB的上调通过直接与IRβ相互作用，从而损害心脏胰岛素信号传导，从而增加MI/R损伤和心脏功能障碍。
Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-β subunit (IRβ) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdownviaAAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice caused exacerbated MI/R injury and impairment of insulin-mediated signaling. In cultured neonatal mouse cardiomyocytes, incubation of FetB significantly reduced tyrosine kinase activity of IR and insulin-induced glucose uptake, and increased hypoxia/reoxygenation-induced apoptosis. Furthermore, FoxO1 knockdown by siRNA suppressed FetB expressions in hepatocytes treated with palmitic acid. In conclusion, upregulated FetB in diabetic liver contributes to increased MI/R injury and cardiac dysfunctionviadirectly interacting with IRβ and consequently impairing cardiac insulin signaling.