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

Abstract

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.

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

“…The site specificity of ER stress at RVLM in the manifestation of hypertension is confirmed by observations that microinjection of tunicamycin to areas outside the confines of RVLM did not affect MAP in normotensive WKY rats. We noted that methods used for quantitative analysis of eIF2α phosphorylation are controversial; both SDS-PAGE 38 and Phos-tag gel 39 have been reported in the literature. Thus, we included analysis by Phos-tag gels in the present study to validate the results obtained from the conventional SDS-PAGE used in Western blot analysis.…”

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

“…ER stress causes insulin resistance and participates in the low-grade inflammation observed in insulin resistant states [13,20] by mediating cell death and the activation of inflammatory pathways such as nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) [15]. An association between ER stress and endothelial dysfunction was reported in experimental models of diabetes [14,21]; however, the underpinning mechanisms are unclear especially regarding the role of ER-stress mediated inflammation and cell death.…”

Tauroursodeoxycholic acid attenuates inorganic phosphate-induced osteoblastic differentiation and mineralization in NIH3T3 fibroblasts by inhibiting the ER stress response PERK-eIF2α-ATF4 pathway

“…ATF4 has been proven to be a critical transcription factor downstream of PERK signaling branches of ER stress, ATF4 can not regulate osteocalcin and bone sialoprotein transcription but also preserves mature osteoblast function including the synthesis of collagen, the most abundant extracellular protein found in bones (15). As a classical ER stress inhibitor, TUDCA has been proven to decrease the expression of phosphorylated eIF2α and ATF4 (16)(17)(18)(19)(20)(21)(22). In a recent study, Zhejun Cai et al (23), found that TUDCA protected against oxLDL-induced ER stress in VICs, significantly suppressed osteoblastic differentiation and protected against hypercholesterolemia-induced AV calcification in animal models.…”

“…It has been proved that TUDCA can enhance ER folding ability to prevent protein aggregation and thus protect cells against ER stress (16). TUDCA has been widely used in treatment of disease, such as, cholelithiasis, cholestatic liver disease, diabetes mellitus, obesity, and atherosclerosis, it works via preventing ER stress, as a classical ER stress inhibitor (17)(18)(19)(20)(21)(22). Studies have demonstrated that TUDCA could markedly prevent Aortic valve (AV) calcification, and attenuate AV osteoblastic differentiation in both rabbit and mouse models of AV calcification via inhibition of ER stress and could suppress oxidized low density lipoprotein (oxLDL)-induced osteoblastic differentiation in cultured valvular interstitial cells (VICs) (23) and could alleviate advanced glycation end product-induced apoptosis and osteoblastic differentiation of stromal cells via alleviating ER stress (22,24).…”