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Inhibition of Epidermal Growth Factor Receptor Tyrosine Kinase and Endoplasmic Reticulum Stress Protects Myocardial from Ischemia ‐ Reperfusion Injury in Type 2 Diabetic Mice
Author(s) -
Mali Vishal R.,
Ali Maha,
Haddox Samuel,
Matrougui Khalid,
Belmadani Souad
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.729.3
Subject(s) - cardioprotection , tauroursodeoxycholic acid , medicine , endocrinology , reperfusion injury , unfolded protein response , endoplasmic reticulum , ischemia , chop , pharmacology , biology , microbiology and biotechnology , chemotherapy
Background We previously reported that epidermal growth factor receptor tyrosine kinase (EGFRtk) activity and endoplasmic reticulum (ER) stress are enhanced in type 2 diabetic mice and cause vascular dysfunction. In the present study, we determined the in vivo contribution of EGFRtk and ER stress in acute myocardial infarction in type 2 diabetic (db−/db−) mice. Methods and Results We treated type 2 diabetic mice (db−/db−) mice with EGFRtk inhibitor (AG1478, 10 mg/kg/day) or ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) for two weeks. After the treatment, mice were subjected to myocardial ischemia for 40 minutes and followed by reperfusion for 24 hours. The treatment with AG1478 and TUDCA reduced infarct size illustrating a cardioprotection effect of inhibiting EGFRtk signaling or ER stress against ischemia‐reperfusion injury in type 2 diabetic mice. To determine the signaling mechanism responsible for the observed cardioprotection, we determined the level of ER stress proteins Chop and BIP expression. The AG1478 or TUDCA significantly decreased the expression of BIP and Chop in diabetic mice compared to untreated db−/db− mice. Also, AG1478 and TUDCA reduced cardiomyocyte apoptosis, p38, and ERK1/2 MAP‐Kinases, and increased the activity of the pro‐survival signaling cascade Akt. Immunohistochemistry staining showed that EGFRtk inhibition and TUDCA treatment lowered macrophages and neutrophil infiltration after I/R injury in diabetic hearts compared to untreated mice. Conclusion Overall, we showed for the first time that inhibition of EGFRtk and ER stress protect diabetic mice against ischemia‐reperfusion injury by activating the reperfusion injury survival pathway and inhibiting apoptotic signaling and inflammation. These findings suggest the importance of targeting ER stress and EGFRtk as a potential therapy for heart complication in type 2 diabetes. Support or Funding Information This study was supported by EVMS Research Enhance Grant