Department of Physiological Sciences, EVMS, Norfolk, VA, 23501, USA.
Pflugers Arch. 2018 Mar;470(3):471-480. doi: 10.1007/s00424-017-2097-5. Epub 2017 Dec 29.
We previously reported that EGFR tyrosine kinase (EGFRtk) activity and endoplasmic reticulum (ER) stress are enhanced in type 2 diabetic (T2D) mice and cause vascular dysfunction. In the present study, we determined the in vivo contribution of EGFRtk and ER stress in acute myocardial infarction induced by acute ischemia (40 min)-reperfusion (24 h) (I/R) injury in T2D (db/db) mice. We treated db/db mice with EGFRtk inhibitor (AG1478, 10 mg/kg/day) for 2 weeks. Mice were then subjected to myocardial I/R injury. The db/db mice developed a significant infarct after I/R injury. The inhibition of EGFRtk significantly reduced the infarct size and ER stress induction. We also determined that the inhibition of ER stress (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) in db/db significantly decrease the infarct size indicating that ER stress is a downstream mechanism to EGFRtk. Moreover, AG1478 and TUDCA reduced myocardium p38 and ERK1/2 MAP-kinases activity, and increased the activity of the pro-survival signaling cascade Akt. Additionally, the inhibition of EGFRtk and ER stress reduced cell apoptosis and the inflammation as indicated by the reduction in macrophages and neutrophil infiltration. We determined for the first time that the inhibition of EGFRtk protects T2D heart against I/R injury through ER stress-dependent mechanism. The cardioprotective effect of EGFRtk and ER stress inhibition involves the activation of survival pathway, and inhibition of apoptosis, and inflammation. Thus, targeting EGFRtk and ER stress has the potential for therapy to overcome myocardial infarction in T2D.
我们之前曾报道过，2 型糖尿病（T2D）小鼠的表皮生长因子受体酪氨酸激酶（EGFRtk）活性和内质网（ER）应激增强，导致血管功能障碍。在本研究中，我们确定了 EGFRtk 和 ER 应激在急性缺血（40 分钟）-再灌注（24 小时）（I/R）损伤诱导的 T2D（db/db）小鼠急性心肌梗死中的体内作用。我们用 EGFRtk 抑制剂（AG1478，10mg/kg/天）处理 db/db 小鼠 2 周。然后，将小鼠进行心肌 I/R 损伤。db/db 小鼠在 I/R 损伤后发生明显的梗死。EGFRtk 的抑制显著减少了梗死面积和 ER 应激诱导。我们还确定，db/db 中 ER 应激（牛磺熊脱氧胆酸，TUDCA，150mg/kg/天）的抑制显著减少了梗死面积，表明 ER 应激是 EGFRtk 的下游机制。此外，AG1478 和 TUDCA 降低了心肌 p38 和 ERK1/2 MAP 激酶活性，并增加了促生存信号级联 Akt 的活性。此外，EGFRtk 和 ER 应激的抑制减少了细胞凋亡和炎症，表现为巨噬细胞和中性粒细胞浸润减少。我们首次确定，通过依赖 ER 应激的机制，EGFRtk 的抑制可保护 T2D 心脏免受 I/R 损伤。EGFRtk 和 ER 应激抑制的心脏保护作用涉及生存途径的激活，以及凋亡和炎症的抑制。因此，靶向 EGFRtk 和 ER 应激有可能用于治疗 T2D 中的心肌梗死。
