A novel role for epidermal growth factor receptor tyrosine kinase and its downstream endoplasmic reticulum stress in cardiac damage and microvascular dysfunction in type 1 diabetes mellitus.
A novel role for epidermal growth factor receptor tyrosine kinase and its downstream endoplasmic reticulum stress in cardiac damage and microvascular dysfunction in type 1 diabetes mellitus.
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DOI：
10.1161/hypertensionaha.112.192500
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Matrougui K
中科院分区：
文献类型：
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作者：
Galán M;Kassan M;Choi SK;Partyka M;Trebak M;Henrion D;Matrougui K
表皮生长因子受体酪氨酸激酶（EGFRtk）和内质网（ER）应激是心血管并发症的重要因素。了解增强的EGFRtk活性和ER应激诱导是否参与1型糖尿病的心脏损伤和微血管功能障碍是一个尚未回答的重要问题。在仅注射链脲佐菌素或与EGFRtk抑制剂（AG 1478）、ER应激抑制剂（Tudca）或胰岛素组合注射2周的C57 BL/6 J小鼠中测定心脏纤维化和微血管功能。在糖尿病小鼠中，我们观察到心脏和肠系膜阻力动脉中EGFRtk磷酸化和ER应激标志物表达（CHOP、ATF 4、ATF 6和磷酸化eIF 2 α）增加，而AG 1478、Tudca和胰岛素则降低。AG 1478、Tudca和胰岛素治疗可降低心脏纤维化、I型胶原增强和纤溶酶原激活物抑制剂1。受损的内皮依赖性舒张和非依赖性舒张反应也恢复治疗后。NO合成的抑制降低了对照组和链脲佐菌素治疗组小鼠的内皮依赖性舒张，而NADPH氧化酶的抑制仅改善了链脲佐菌素治疗组小鼠的内皮依赖性舒张。此外，在肠系膜阻力动脉中，Nox 2和Nox 4的mRNA水平和NADPH氧化酶活性在链脲佐菌素小鼠中增加，并随着治疗而减少。这项研究揭示了增强的EGFRtk磷酸化及其下游ER应激在1型糖尿病心脏纤维化和微血管内皮功能障碍中的新作用。
Epidermal growth factor receptor tyrosine kinase (EGFRtk) and endoplasmic reticulum (ER) stress are important factors in cardiovascular complications. Understanding whether enhanced EGFRtk activity and ER stress induction are involved in cardiac damage, and microvascular dysfunction in type 1 diabetes mellitus is an important question that has remained unanswered. Cardiac fibrosis and microvascular function were determined in C57BL/6J mice injected with streptozotocin only or in combination with EGFRtk inhibitor (AG1478), ER stress inhibitor (Tudca), or insulin for 2 weeks. In diabetic mice, we observed an increase in EGFRtk phosphorylation and ER stress marker expression (CHOP, ATF4, ATF6, and phosphorylated-eIF2α) in heart and mesenteric resistance arteries, which were reduced with AG1478, Tudca, and insulin. Cardiac fibrosis, enhanced collagen type I, and plasminogen activator inhibitor 1 were decreased with AG1478, Tudca, and insulin treatments. The impaired endothelium-dependent relaxation and -independent relaxation responses were also restored after treatments. The inhibition of NO synthesis reduced endothelium-dependent relaxation in control and treated streptozotocin mice, whereas the inhibition of NADPH oxidase improved endothelium-dependent relaxation only in streptozotocin mice. Moreover, in mesenteric resistance arteries, the mRNA levels of Nox2 and Nox4 and the NADPH oxidase activity were augmented in streptozotocin mice and reduced with treatments. This study unveiled novel roles for enhanced EGFRtk phosphorylation and its downstream ER stress in cardiac fibrosis and microvascular endothelial dysfunction in type 1 diabetes mellitus.