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Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes

  • Integrative Physiology
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Abstract

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.

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References

  1. Akhtar S, Yousif MH, Chandrasekhar B, Benter IF (2012) Activation of EGFR/ERBB2 via pathways involving ERK1/2, P38 MAPK, AKT and FOXO enhances recovery of diabetic hearts from ischemia-reperfusion injury. PLoS One 7:e39066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Amin A, Choi SK, Galan M, Kassan M, Partyka M, Kadowitz P, Henrion D, Trebak M, Belmadani S, Matrougui K (2012) Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice. J Pathol 227:165–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Barrett-Connor E, Orchard TJ (1985) Insulin-dependent diabetes mellitus and ischemic heart disease. Diabetes Care 8(Suppl 1):65–70

    Article  PubMed  Google Scholar 

  4. Barrick CJ, Roberts RB, Rojas M, Rajamannan NM, Suitt CB, O'Brien KD, Smyth SS, Threadgill DW (2009) Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice. Am J Phys Heart Circ Phys 297:H65–H75

    CAS  Google Scholar 

  5. Belmadani S, Palen DI, Gonzalez-Villalobos RA, Boulares HA, Matrougui K (2008) Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db/db mice. Diabetes 57:1629–1637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bhagat K (1998) Endothelial function and myocardial infarction. Cardiovasc Res 39:312–317

    Article  CAS  PubMed  Google Scholar 

  7. Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57:660–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ (2008) Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 57:696–705

    Article  CAS  PubMed  Google Scholar 

  9. Choi S-K, Galán M, Partyka M, Trebak M, Belmadani S, Matrougui K (2012) Chronic inhibition of epidermal growth factor receptor tyrosine kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2) augments vascular response to limb ischemia in type 2 diabetic mice. Am J Pathol 180:410–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, Kaufman RJ, Chevet E, Bikfalvi A, Moenner M (2007) IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 67:6700–6707

    Article  CAS  PubMed  Google Scholar 

  11. Feng M, Xiang J-Z, Ming Z-Y, Fu Q, Ma R, Zhang Q-F, Dun Y-Y, Yang L, Liu H (2012) Activation of epidermal growth factor receptor mediates reperfusion arrhythmias in anaesthetized rats. Cardiovasc Res 93:60–68

    Article  CAS  PubMed  Google Scholar 

  12. Galan M, Kassan M, Choi SK, Partyka M, Trebak M, Henrion D, Matrougui K (2012) 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. Hypertension 60:71–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greer JJ, Ware DP, Lefer DJ (2006) Myocardial infarction and heart failure in the db/db diabetic mouse. Am J Physiol Heart Circ Physiol 290:H146–H153

    Article  CAS  PubMed  Google Scholar 

  14. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr, Sowers JR (1999) Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100:1134–1146

    Article  CAS  PubMed  Google Scholar 

  15. Gundewar S, Calvert JW, Elrod JW, Lefer DJ (2007) Cytoprotective effects of N,N,N-trimethylsphingosine during ischemia-reperfusion injury are lost in the setting of obesity and diabetes. Am J Physiol Heart Circ Physiol 293:H2462–H2471

    Article  CAS  PubMed  Google Scholar 

  16. Hammoud L, Lu X, Lei M, Feng Q (2011) Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. Basic Res Cardiol 106:459–471

    Article  CAS  PubMed  Google Scholar 

  17. Huxley R, Barzi F, Woodward M (2006) Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332:73–78

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jacoby RM, Nesto RW (1992) Acute myocardial infarction in the diabetic patient: pathophysiology, clinical course and prognosis. J Am Coll Cardiol 20:736–744

    Article  CAS  PubMed  Google Scholar 

  19. Jamroz-Wisniewska A, Wojcicka G, Lowicka E, Ksiazek M, Beltowski J (2008) Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia: role in leptin-induced hypertension. Biochem Pharmacol 75:1623–1638

    Article  CAS  PubMed  Google Scholar 

  20. Kagiyama S, Eguchi S, Frank GD, Inagami T, Zhang YC, Phillips MI (2002) Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense. Circulation 106:909–912

    Article  CAS  PubMed  Google Scholar 

  21. Kassan M, Galan M, Choi SK, and Matrougui K (2011) Endoplasmic reticulum stress and microvascular endothelial dysfunction in diabetes. J Diabetes Metab 2

  22. Kassan M, Choi SK, Galan M, Bishop A, Umezawa K, Trebak M, Belmadani S, Matrougui K (2013) Enhanced NF-kappaB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. Diabetes 62:2078–2087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kharroubi AT, Darwish HM (2015) Diabetes mellitus: the epidemic of the century. World J Diabetes 6:850–867

    Article  PubMed  PubMed Central  Google Scholar 

  24. Konishi A, Berk BC (2003) Epidermal growth factor receptor transactivation is regulated by glucose in vascular smooth muscle cells. J Biol Chem 278:35049–35056

    Article  CAS  PubMed  Google Scholar 

  25. Laakso M (2001) Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention. J Intern Med 249:225–235

    Article  CAS  PubMed  Google Scholar 

  26. Lambert JP, Nicholson CK, Amin H, Amin S, Calvert JW (2014) Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Med Gas Res 4:20

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, Donmez G, Li J, Luo Z, Walsh K, Guarente L, Zang M (2011) Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J 25:1664–1679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li W, Fang Q, Zhong P, Chen L, Wang L, Zhang Y, Wang J, Li X, Wang Y, Wang J (2016) EGFR inhibition blocks palmitic acid-induced inflammation in cardiomyocytes and prevents hyperlipidemia-induced cardiac injury in mice. Sci Rep 6:24580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liang D, Zhong P, Hu J, Lin F, Qian Y, Xu Z, Wang J, Zeng C, Li X, Liang G (2015) EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. J Mol Cell Cardiol 82:63–74

    Article  CAS  PubMed  Google Scholar 

  30. Luetteke NC, Phillips HK, Qiu TH, Copeland NG, Earp HS, Jenkins NA, Lee DC (1994) The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev 8:399–413

    Article  CAS  PubMed  Google Scholar 

  31. Matrougui K (2010) Diabetes and microvascular pathophysiology: role of epidermal growth factor receptor tyrosine kinase. Diabetes Metab Res Rev 26:13–16

    Article  PubMed  PubMed Central  Google Scholar 

  32. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J (1998) Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care 21:69–75

    Article  CAS  PubMed  Google Scholar 

  33. Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T, Terashima Y, Takada A, Ishikawa S, Shimamoto K (2009) Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 58:2863–2872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mocanu MM, Field DC, Yellon DM (2006) A potential role for PTEN in the diabetic heart. Cardiovasc Drugs Ther 20:319–321

    Article  PubMed  Google Scholar 

  35. Ozawa K, Miyazaki M, Matsuhisa M, Takano K, Nakatani Y, Hatazaki M, Tamatani T, Yamagata K, Miyagawa J, Kitao Y, Hori O, Yamasaki Y, Ogawa S (2005) The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. Diabetes 54:657–663

    Article  CAS  PubMed  Google Scholar 

  36. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    Article  PubMed  PubMed Central  Google Scholar 

  37. Poornima IG, Parikh P, Shannon RP (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98:596–605

    Article  CAS  PubMed  Google Scholar 

  38. Song P, Wu Y, Xu J, Xie Z, Dong Y, Zhang M, Zou MH (2007) Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation 116:1585–1595

    Article  CAS  PubMed  Google Scholar 

  39. Taniguchi K, Xia L, Goldberg HJ, Lee KW, Shah A, Stavar L, Masson EA, Momen A, Shikatani EA, John R, Husain M, Fantus IG (2013) Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. Diabetes 62:3874–3886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Touyz RM, Wu XH, He G, Salomon S, Schiffrin EL (2002) Increased angiotensin II-mediated Src signaling via epidermal growth factor receptor transactivation is associated with decreased C-terminal Src kinase activity in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 39:479–485

    Article  CAS  PubMed  Google Scholar 

  41. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350

    Article  CAS  PubMed  Google Scholar 

  42. Wang B, Raedschelders K, Shravah J, Hui Y, Safaei HG, Chen DD, Cook RC, Fradet G, Au CL, Ansley DM (2011) Differences in myocardial PTEN expression and Akt signalling in type 2 diabetic and nondiabetic patients undergoing coronary bypass surgery. Clin Endocrinol 74:705–713

    Article  CAS  Google Scholar 

  43. Zhou J, Du T, Li B, Rong Y, Verkhratsky A, and Peng L (2015) Crosstalk between MAPK/ERK and PI3K/AKT signal pathways during brain ischemia/reperfusion. ASN Neuro 7

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Funding

This work was supported by NIH-R01HL095566 (KM) and Research Emphasis Grant (EVMS; SB).

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Authors and Affiliations

  1. Department of Physiological Sciences, EVMS, Norfolk, VA, 23501, USA

    Vishal Mali, Samuel Haddox, Corey Hornersmith, Khalid Matrougui & Souad Belmadani

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  1. Vishal Mali
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  2. Samuel Haddox
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  3. Corey Hornersmith
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  4. Khalid Matrougui
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  5. Souad Belmadani
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Corresponding author

Correspondence to Souad Belmadani.

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All experimental mice procedures were performed according to the American Guidelines for the Ethical Care of Animals and approved by the Institutional Animal Care and Use Committee at Eastern Virginia Medical School.

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The authors declare that they have no conflict of interest.

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Mali, V., Haddox, S., Hornersmith, C. et al. Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes. Pflugers Arch - Eur J Physiol 470, 471–480 (2018). https://doi.org/10.1007/s00424-017-2097-5

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  • DOI: https://doi.org/10.1007/s00424-017-2097-5

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