Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.
J Mol Cell Cardiol. 2015 May;82:63-74. doi: 10.1016/j.yjmcc.2015.02.029. Epub 2015 Mar 7.
Diabetes mellitus is strongly associated with cardiomyopathy. The underlying mechanisms for the development of diabetic cardiomyopathy are complex and not completely understood. Recent studies showed that epidermal growth factor receptors (EGFRs) are involved in diabetes-induced cardiac injury. However, the role of EGFR in the diabetic heart has yet to be confirmed. The aim of the present study is to further determine the role of EGRF in the pathogenesis of diabetic heart injury. The type 1 diabetic mice induced by streptozotocin were treated with EGFR inhibitors (AG1478 and 451) for 8 weeks, respectively. It was observed that diabetes induced phospohorylation of EGFR and AKT, increased cardiac ROS levels, and ultimately led to cardiac remodeling including cardiac hypertrophy, disorganization, apoptosis, and fibrosis, while all these molecular and pathological alterations were attenuated by the treatment with EGFR inhibitors. In vitro, either pharmacological inhibition of EGFR/AKT or sh-RNA silencing of EGFR significantly inhibited high concentration glucose (HG)-induced ROS generation and subsequently cell apoptosis in both cardiac H9C2 cells and primary rat cardiomyocytes, respectively. The ROS reduction by EGFR inhibitor was associated with the decreased NADPH oxidase activity and expression in H9c2 cells. HG-induced cardiomyocyte injuries were also reduced by NAC, an inhibitor of ROS. This study provides evidence that EGFR has a key role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling via ROS generation, and suggests that EGFR may be a potential target in treating diabetic cardiomyopathy.
糖尿病与心肌病密切相关。糖尿病心肌病发展的潜在机制复杂，尚未完全阐明。最近的研究表明，表皮生长因子受体（EGFRs）参与了糖尿病引起的心脏损伤。然而，EGFR 在糖尿病心脏中的作用尚未得到证实。本研究旨在进一步确定 EGFR 在糖尿病心脏损伤发病机制中的作用。分别用 EGFR 抑制剂（AG1478 和 451）处理链脲佐菌素诱导的 1 型糖尿病小鼠 8 周。结果观察到糖尿病诱导 EGFR 和 AKT 的磷酸化，增加心脏 ROS 水平，最终导致心脏重构，包括心脏肥大、紊乱、细胞凋亡和纤维化，而所有这些分子和病理改变均被 EGFR 抑制剂的治疗所减轻。在体外，EGFR/AKT 的药理学抑制或 EGFR 的 sh-RNA 沉默均显著抑制高浓度葡萄糖（HG）诱导的心脏 H9C2 细胞和原代大鼠心肌细胞中 ROS 的产生和随后的细胞凋亡。EGFR 抑制剂降低 ROS 与 H9c2 细胞中 NADPH 氧化酶活性和表达的降低有关。HG 诱导的心肌细胞损伤也被 ROS 抑制剂 NAC 减轻。本研究提供的证据表明，EGFR 通过 ROS 的产生在 STZ 诱导的糖尿病心脏损伤和重构的发病机制中起关键作用，并表明 EGFR 可能是治疗糖尿病心肌病的潜在靶点。
