Dokument: Einfluss von Insulin und chronisch oxidativem Stress auf die endotheliale Funktion – Rolle der endothelialen Stickstoffmonoxid-Synthase
| Titel: | Einfluss von Insulin und chronisch oxidativem Stress auf die endotheliale Funktion – Rolle der endothelialen Stickstoffmonoxid-Synthase | |||||||
| Weiterer Titel: | Role of Insulin Mediated Pathway and Chronic Oxidative Stress on Endothelial Function | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=54445 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20201026-085513-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dirzka, Jennifer [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Dr. rer. nat. Cortese-Krott, Miriam [Gutachter] Prof. Dr. Grandoch, Maria [Gutachter] | |||||||
| Stichwörter: | eNOS, Insulin, Nrf2 | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Hintergrund und Ziel. Kennzeichnend für kardiovaskuläre Erkrankungen ist die endotheliale Dysfunktion, welche durch den Rückgang der Bioaktivität der endothelialen Stickstoffmonoxid-Synthase (eNOS), und damit eine verminderte Produktion von Stickstoffmonoxid (NO) und erhöhten oxidativen Stress gekennzeichnet ist. Ziel des Projektes ist die ex-vivo und in-vivo Untersuchung der endothelialen Funktion anhand von Mausmodellen, die sich durch Fehlregulation der Redox-Reaktionen auszeichnen. Mausmodelle. Bei Mäusen, die keinen Transkriptionsfaktor Nrf2 (Nrf2 Knockout Maus) exprimieren, kann das Modell der chronischen Adaptation an oxidativen Stress studiert werden. Fehlregulation von Redox-Reaktionen aufgrund von Typ-II-Diabetes mellitus ist ebenfalls mit der Entwicklung von endothelialer Dysfunktion assoziiert, was im Mausmodell des Typ-II-Diabetes mellitus (New Zealand Obesity Maus) untersucht werden kann. Es wurde weiterhin gezeigt, dass Hyperinsulinämie die eNOS-Aktivität durch Phosphorylierung von Tyrosin 657 via proline-rich tyrosine kinase 2 (Pyk2) vermindert; es erfolgte für das Mausmodell des Typ-II-Diabetes mellitus zusätzlich die Gabe eines Pyk2-Inhibitors. Methoden. Im Rahmen von ex-vivo Versuchen wurden isolierte Aorten von männlichen Nrf2 KO, NZO und Wildtyp Mäusen (WT) im Alter von 20 Wochen mithilfe eines Myographen untersucht. Konzentrationsabhängige Analysen wurden nach Gabe von Acetylcholin (ACh), Phenylephrin (PHE) und Nitroprussid-Natrium (SNP) erstellt. Insulin ELISA wurden zum Beleg der Hyperinsulinämie bei NZO verwendet und die eNOS-Expression mithilfe Western Blot Analyse ausgewertet. Die Untersuchung der endothelialen Funktion in-vivo erfolgte mit Ultraschall nach „ischämischer Fern(prä)konditionierung“ (remote ischemic preconditioning) im Rahmen von flussmediierter Vasodilatation (FMD). Ergebnisse. In den ex-vivo Untersuchungen ergab sich für die Nrf2 KO eine erhaltene endotheliale Funktion. Derweil präsentierten die NZO eine verminderte endotheliale Funktion mit beeinträchtigter Vasodilatation, wohingegen die Pyk2-Inhibition in NZO in eine partielle Wiederherstellung der endothelialen Funktion resultierte. Die Insulin Level waren bei allen NZO unabhängig von der Pyk2-Inhibitor Applikation erhöht. Schlussfolgerung. In Nrf2 KO scheint die Fehlregulation der Redox-Reaktionen durch eine kompensatorische Hochregulation der eNOS in der Aorta ausgeglichen zu werden. Die Hyperinsulinämie in NZO korreliert mit endothelialer Dysfunktion, wohingegen die Hemmung der Pyk2 zur partiellen Wiederherstellung der endothelialen Funktion führt.Background and Aim. Endothelial dysfunction is regarded as a hallmark of CVD and is characterized by multifactorial changes in the vessel wall, leading to decreased bioactivity of the endothelial nitric oxide synthase (eNOS), reduced production of nitric oxide (NO) and increased oxidative stress. In this study we aimed to investigate the endothelial function ex vivo and in vivo in mice models of redox dysregulation. Mice Models. The transcription factor Nrf2 controls the expression of antioxidant and protective enzymes. Thus mice lacking the transcription factor Nrf2 (Nrf2 knock out mice) are considered as a model of chronic adaptation of the organism to oxidative stress. Redox dysregulation due to diabetes type II and the metabolic syndrome are also associated with the development of endothelial dysfunction. Further recent studies demonstrated that hyperinsulinemia inhibits eNOS activity by phosphorylation on Tyrosin 657 via proline-rich tyrosine kinase 2 (Pyk2); therefore Pyk2 inhibitor was applied to a diabetes type II specified mouse model (NZO). Methods. Isolated aorta of male Nrf2 KO mice, NZO mice and wild type mice (WT) each approximately 20 weeks of age were studied ex vivo using a myograph. Concentration-response curves to acetylcholine (ACh), phenylephrine (PHE) and sodium nitro prusside (SNP) were performed. Endothelium-dependent relaxation was assessed by measuring the reactive dilatation to ACh in PHE-precontracted vessels. The effect of Pyk2 inhibitor on eNOS regulation was examined after administration of the inhibitor to NZO. To prove hyperinsulinemia in NZO insulin levels were measured with Insulin ELISA and to measure eNOS activity Western Blot analysis was used. In vivo assessment of endothelial function was done by flow-mediated dilation (FMD) by applying remote ischemic preconditioning to iliac vessels. Results. Nrf2 KO showed ex vivo a fully preserved endothelial function. NZO in absence of Pyk2 inhibitor presented a significantly decreased endothelial function with impaired vasodilation to ACh in comparison to WT whereas insulin levels were significantly increased. In presence of Pyk2 inhibitor NZO presented ex vivo and in vivo a regain of endothelial function. Conclusion. These results point to a significant role of eNOS in the regulation of endothelial function. In Nrf2 KO the endothelial function is preserved by up-regulation of eNOS in the aorta shown by our Western Blot analysis. Increased insulin levels in NZO are correlated to endothelial dysfunction whereas Pyk2 inhibition results in partial regain of endothelial function ex vivo and in vivo. | |||||||
| Quelle: | 1. Nichols, M., et al., Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J, 2014. 35(42): p. 2929.
2. Roth, G.A., et al., Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med, 2015. 372(14): p. 1333-41. 3. Reynolds, L.R., et al., Differential effects of rosiglitazone and insulin glargine on inflammatory markers, glycemic control, and lipids in type 2 diabetes. Diabetes Res Clin Pract, 2007. 77(2): p. 180-7. 4. Ross, R., J. Glomset, and L. Harker, Response to injury and atherogenesis. Am J Pathol, 1977. 86(3): p. 675-84. 5. Napoli, C., et al., Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest, 1997. 100(11): p. 2680-90. 6. Balletshofer, B.M., et al., Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation, 2000. 101(15): p. 1780-4. 7. Schulz, E., et al., Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid Redox Signal, 2008. 10(6): p. 1115-26. 8. Heiss, C., et al., In vivo measurement of flow-mediated vasodilation in living rats using high-resolution ultrasound. Am J Physiol Heart Circ Physiol, 2008. 294(2): p. H1086-93. 9. Jerie, P., [Milestones of cardiovascular therapy. III. Nitroglycerin]. Cas Lek Cesk, 2007. 146(6): p. 533-7. 10. Marsh, N. and A. Marsh, A short history of nitroglycerine and nitric oxide in pharmacology and physiology. Clin Exp Pharmacol Physiol, 2000. 27(4): p. 313-9. 11. Ignarro, L.J., Physiological significance of endogenous nitric oxide. Semin Perinatol, 1991. 15(1): p. 20-6. 12. Star, R.A., Nitric oxide. Am J Med Sci, 1993. 306(5): p. 348-58. 13. Lancaster, J.R., Jr., A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide, 1997. 1(1): p. 18-30. 14. Rubanyi, G.M., J.C. Romero, and P.M. Vanhoutte, Flow-induced release of endothelium-derived relaxing factor. Am J Physiol, 1986. 250(6 Pt 2): p. H1145-9. 15. Busse, R., et al., Endothelial cells are involved in the vasodilatory response to hypoxia. Pflugers Arch, 1983. 397(1): p. 78-80. 16. Rubanyi, G.M. and P.M. Vanhoutte, Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol, 1986. 250(5 Pt 2): p. H822-7. 17. Fleming, I., et al., Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci, 2005. 118(Pt 18): p. 4103-11. 18. Azuma, H., M. Ishikawa, and S. Sekizaki, Endothelium-dependent inhibition of platelet aggregation. Br J Pharmacol, 1986. 88(2): p. 411-5. 19. Kroncke, K.D., K. Fehsel, and V. Kolb-Bachofen, Inducible nitric oxide synthase and its product nitric oxide, a small molecule with complex biological activities. Biol Chem Hoppe Seyler, 1995. 376(6): p. 327-43. 20. Kroncke, K.D., et al., Inducible nitric oxide synthase-derived nitric oxide in gene regulation, cell death and cell survival. Int Immunopharmacol, 2001. 1(8): p. 1407-20. 21. Arnold, W.P., et al., Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A, 1977. 74(8): p. 3203-7. 22. Green, L.C., S.R. Tannenbaum, and P. Goldman, Nitrate synthesis in the germfree and conventional rat. Science, 1981. 212(4490): p. 56-8. 23. Cosby, K., et al., Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med, 2003. 9(12): p. 1498-505. 24. Nagababu, E., et al., Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J Biol Chem, 2003. 278(47): p. 46349-56. 25. Hendgen-Cotta, U.B., et al., Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A, 2008. 105(29): p. 10256-61. 26. Rassaf, T., et al., Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res, 2007. 100(12): p. 1749-54. 27. Furchgott, R.F. and J.V. Zawadzki, The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 1980. 288(5789): p. 373-6. 28. Forstermann, U., et al., Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries. Circ Res, 1986. 58(4): p. 531-8. 29. Ignarro, L.J., et al., Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J Pharmacol Exp Ther, 1986. 237(3): p. 893-900. 30. Ignarro, L.J., et al., Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res, 1987. 61(6): p. 866-79. 31. Palmer, R.M., A.G. Ferrige, and S. Moncada, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 1987. 327(6122): p. 524-6. 32. Moncada, S., R.M. Palmer, and E.A. Higgs, Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol, 1989. 38(11): p. 1709-15. 33. Moncada, S. and R.M. Palmer, Biosynthesis and actions of nitric oxide. Semin Perinatol, 1991. 15(1): p. 16-9. 34. Chapman, A.L., et al., Ceruloplasmin is an endogenous inhibitor of myeloperoxidase. J Biol Chem, 2013. 288(9): p. 6465-77. 35. Furchgott, R.F., et al., Endothelial cells as mediators of vasodilation of arteries. J Cardiovasc Pharmacol, 1984. 6 Suppl 2: p. S336-43. 36. Forstermann, U., et al., Isoforms of nitric-oxide synthase: purification and regulation. Methods Enzymol, 1994. 233: p. 258-64. 37. Busse, R. and A. Mulsch, Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett, 1990. 265(1-2): p. 133-6. 38. Bredt, D.S. and S.H. Snyder, Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A, 1990. 87(2): p. 682-5. 39. Bredt, D.S., et al., Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature, 1991. 351(6329): p. 714-8. 40. Xu, K.Y., et al., Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci U S A, 1999. 96(2): p. 657-62. 41. Forstermann, U., et al., Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension, 1994. 23(6 Pt 2): p. 1121-31. 42. Izumi, Y., D.B. Clifford, and C.F. Zorumski, Inhibition of long-term potentiation by NMDA-mediated nitric oxide release. Science, 1992. 257(5074): p. 1273-6. 43. Togashi, H., et al., A central nervous system action of nitric oxide in blood pressure regulation. J Pharmacol Exp Ther, 1992. 262(1): p. 343-7. 44. Lipton, S.A., et al., A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature, 1993. 364(6438): p. 626-32. 45. Nathan, C.F. and J.B. Hibbs, Jr., Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol, 1991. 3(1): p. 65-70. 46. Ischiropoulos, H., L. Zhu, and J.S. Beckman, Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys, 1992. 298(2): p. 446-51. 47. Langrehr, J.M., et al., Nitric oxide synthesis in the in vivo allograft response: a possible regulatory mechanism. Surgery, 1991. 110(2): p. 335-42. 48. MacMicking, J.D., et al., Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell, 1995. 81(4): p. 641-50. 49. Forstermann, U., J.P. Boissel, and H. Kleinert, Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J, 1998. 12(10): p. 773-90. 50. Dimmeler, S. and A.M. Zeiher, Nitric oxide-an endothelial cell survival factor. Cell Death Differ, 1999. 6(10): p. 964-8. 51. Wood, K.C., et al., Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. Arterioscler Thromb Vasc Biol, 2013. 33(8): p. 1861-71. 52. Simon, A., et al., Role of neutral amino acid transport and protein breakdown for substrate supply of nitric oxide synthase in human endothelial cells. Circ Res, 2003. 93(9): p. 813-20. 53. Sessa, W.C., et al., The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells. Proc Natl Acad Sci U S A, 1990. 87(21): p. 8607-11. 54. Forstermann, U. and W.C. Sessa, Nitric oxide synthases: regulation and function. Eur Heart J, 2012. 33(7): p. 829-37, 837a-837d. 55. Dimmeler, S., et al., Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature, 1999. 399(6736): p. 601-5. 56. Fulton, D., et al., Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature, 1999. 399(6736): p. 597-601. 57. Chalimoniuk, M., et al., Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells. Acta Biochim Pol, 2007. 54(3): p. 611-23. 58. Schneider, J.C., et al., Involvement of Ca2+/calmodulin-dependent protein kinase II in endothelial NO production and endothelium-dependent relaxation. Am J Physiol Heart Circ Physiol, 2003. 284(6): p. H2311-9. 59. Fleming, I., et al., Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res, 2001. 88(11): p. E68-75. 60. Michell, B.J., et al., Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem, 2001. 276(21): p. 17625-8. 61. Davda, R.K., L.J. Chandler, and N.J. Guzman, Protein kinase C modulates receptor-independent activation of endothelial nitric oxide synthase. Eur J Pharmacol, 1994. 266(3): p. 237-44. 62. Fleming, I., Molecular mechanisms underlying the activation of eNOS. Pflugers Arch, 2010. 459(6): p. 793-806. 63. Loot, A.E., et al., Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med, 2009. 206(13): p. 2889-96. 64. Fisslthaler, B., et al., Inhibition of endothelial nitric oxide synthase activity by proline-rich tyrosine kinase 2 in response to fluid shear stress and insulin. Circ Res, 2008. 102(12): p. 1520-8. 65. Bibli, S.I., et al., Tyrosine phosphorylation of eNOS regulates myocardial survival after an ischaemic insult: role of PYK2. Cardiovasc Res, 2017. 66. Yin, G., C. Yan, and B.C. Berk, Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol, 2003. 35(6): p. 780-3. 67. Tai, L.K., et al., Fluid shear stress activates proline-rich tyrosine kinase via reactive oxygen species-dependent pathway. Arterioscler Thromb Vasc Biol, 2002. 22(11): p. 1790-6. 68. Siragusa, M. and B. Fisslthaler, Insulin Keeps PYK-ing on eNOS: Enhanced Insulin Receptor Signaling Induces Endothelial Dysfunction. Circ Res, 2017. 120(5): p. 748-750. 69. Seddon, M., Y.H. Looi, and A.M. Shah, Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart, 2007. 93(8): p. 903-7. 70. Bedard, K. and K.H. Krause, The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev, 2007. 87(1): p. 245-313. 71. Forman, H.J. and M. Torres, Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med, 2002. 166(12 Pt 2): p. S4-8. 72. Li, H., S. Horke, and U. Forstermann, Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis, 2014. 237(1): p. 208-19. 73. McNally, J.S., et al., Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol, 2003. 285(6): p. H2290-7. 74. Heiss, E.H., et al., Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem, 2009. 284(46): p. 31579-86. 75. Li, H. and U. Forstermann, Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol, 2013. 13(2): p. 161-7. 76. Drummond, G.R., et al., Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res, 2000. 86(3): p. 347-54. 77. Lubos, E., et al., Glutathione peroxidase-1 deficiency augments proinflammatory cytokine-induced redox signaling and human endothelial cell activation. J Biol Chem, 2011. 286(41): p. 35407-17. 78. Itoh, K., et al., An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun, 1997. 236(2): p. 313-22. 79. Suzuki, T. and M. Yamamoto, Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med, 2015. 88(Pt B): p. 93-100. 80. Kang, K.W., S.J. Lee, and S.G. Kim, Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal, 2005. 7(11-12): p. 1664-73. 81. Enomoto, A., et al., High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci, 2001. 59(1): p. 169-77. 82. Chen, X.L., et al., Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol, 2006. 290(5): p. H1862-70. 83. Jiang, Z.Y., et al., Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. Journal of Clinical Investigation, 1999. 104(4): p. 447-457. 84. Stehouwer, C.D., et al., Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res, 1997. 34(1): p. 55-68. 85. Cosentino, F., et al., High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation, 1997. 96(1): p. 25-8. 86. Cosentino, F., et al., High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation, 2003. 107(7): p. 1017-23. 87. Tanaka, N., et al., The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factor-kappa B, and by 17beta-estradiol through Sp-1 in human vascular endothelial cells. J Biol Chem, 2000. 275(33): p. 25781-90. 88. Bierhaus, A., et al., AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res, 1998. 37(3): p. 586-600. 89. Bucala, R., K.J. Tracey, and A. Cerami, Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest, 1991. 87(2): p. 432-8. 90. Du, X.L., et al., Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest, 2001. 108(9): p. 1341-8. 91. Laakso, M., Insulin resistance and coronary heart disease. Curr Opin Lipidol, 1996. 7(4): p. 217-26. 92. Group, D.I.S., Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Diabetologia, 2004. 47(7): p. 1245-1256. 93. Kuboki, K., et al., Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo : a specific vascular action of insulin. Circulation, 2000. 101(6): p. 676-81. 94. Tsukahara, H., et al., Experimentally induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: detection using urinary NO2-/NO3-excretion. Metabolism, 1997. 46(4): p. 406-9. 95. Zeng, G.Y. and M.J. Quon, Insulin-stimulated production of nitric oxide is inhibited by wortmannin - Direct measurement in vascular endothelial cells. Journal of Clinical Investigation, 1996. 98(4): p. 894-898. 96. Kashiwagi, S., et al., eNOS phosphorylation on serine 1176 affects insulin sensitivity and adiposity. Biochem Biophys Res Commun, 2013. 431(2): p. 284-90. 97. Steinberg, H.O., et al., Insulin mediated nitric oxide production is impaired in insulin resistance. Diabetes, 1997. 46: p. 92-92. 98. Mather, K., et al., Evidence for physiological coupling of insulin-mediated glucose metabolism and limb blood flow. Am J Physiol Endocrinol Metab, 2000. 279(6): p. E1264-70. 99. Steinberg, H.O., et al., Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes, 2000. 49(7): p. 1231-8. 100. Dresner, A., et al., Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest, 1999. 103(2): p. 253-9. 101. Ferreras, L., et al., Early decrease in GLUT4 protein levels in brown adipose tissue of New Zealand obese mice. Int J Obes Relat Metab Disord, 1994. 18(11): p. 760-5. 102. Harrison, L.C. and A. Itin, A possible mechanism for insulin resistance and hyperglycaemia in NZO mice. Nature, 1979. 279(5711): p. 334-6. 103. Clarke, K.W. and L.W. Hall, "Xylazine"--a new sedative for horses and cattle. Vet Rec, 1969. 85(19): p. 512-7. 104. Pypendop, B.H. and J.P. Verstegen, Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg, 1998. 27(6): p. 612-22. 105. Buckbinder, L., et al., Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A, 2007. 104(25): p. 10619-24. 106. Schwinn, D.A., R.W. McIntyre, and J.G. Reves, Isoflurane-induced vasodilation: role of the alpha-adrenergic nervous system. Anesth Analg, 1990. 71(5): p. 451-9. 107. De Mey, J.G. and P.M. Vanhoutte, Anoxia and endothelium-dependent reactivity of the canine femoral artery. J Physiol, 1983. 335: p. 65-74. 108. Li, J., et al., Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol, 2009. 29(11): p. 1843-50. 109. Tanaka, Y., et al., NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther, 2008. 325(2): p. 655-64. 110. Erkens, R., et al., Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med, 2015. 89: p. 906-17. 111. Gori, T., et al., Conduit artery constriction mediated by low flow a novel noninvasive method for the assessment of vascular function. J Am Coll Cardiol, 2008. 51(20): p. 1953-8. 112. Jyrkkanen, H.K., et al., Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circ Res, 2008. 103(1): p. e1-9. 113. Calvert, J.W., et al., Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res, 2009. 105(4): p. 365-74. 114. Suvorava, T., et al., Endogenous vascular hydrogen peroxide regulates arteriolar tension in vivo. Circulation, 2005. 112(16): p. 2487-95. 115. Suvorava, T. and G. Kojda, Reactive oxygen species as cardiovascular mediators: lessons from endothelial-specific protein overexpression mouse models. Biochim Biophys Acta, 2009. 1787(7): p. 802-10. 116. Balligand, J.L., O. Feron, and C. Dessy, eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev, 2009. 89(2): p. 481-534. 117. d'Uscio, L.V., L.A. Smith, and Z.S. Katusic, Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein e-deficient mice. Stroke, 2001. 32(11): p. 2658-64. 118. Kanazawa, K., et al., Endothelial constitutive nitric oxide synthase protein and mRNA increased in rabbit atherosclerotic aorta despite impaired endothelium-dependent vascular relaxation. Am J Pathol, 1996. 148(6): p. 1949-56. 119. Oemar, B.S., et al., Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation, 1998. 97(25): p. 2494-8. 120. Marchesi, C., et al., Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension, 2009. 54(6): p. 1384-92. 121. Malhotra, A., M.C. Lopez, and A. Nakouzi, Troponin subunits contribute to altered myosin ATPase activity in diabetic cardiomyopathy. Mol Cell Biochem, 1995. 151(2): p. 165-72. 122. Meininger, C.J., et al., Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J, 2000. 349(Pt 1): p. 353-6. 123. Cheng, Z.J., et al., Vascular dysfunction in type 2 diabetic TallyHo mice: role for an increase in the contribution of PGH2/TxA2 receptor activation and cytochrome p450 products. Can J Physiol Pharmacol, 2007. 85(3-4): p. 404-12. 124. Pohl, U., et al., Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension, 1986. 8(1): p. 37-44. 125. Paniagua, O.A., M.B. Bryant, and J.A. Panza, Role of endothelial nitric oxide in shear stress-induced vasodilation of human microvasculature: diminished activity in hypertensive and hypercholesterolemic patients. Circulation, 2001. 103(13): p. 1752-8. 126. Mahmoud, A.M., et al., Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired vascular function. Redox Biol, 2017. 13: p. 288-300. 127. Lee, A.T. and A. Cerami, Role of glycation in aging. Ann N Y Acad Sci, 1992. 663: p. 63-70. 128. Cruickshank, K., et al., Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation, 2002. 106(16): p. 2085-90. 129. Schram, M.T., et al., Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn Study. Hypertension, 2004. 43(2): p. 176-81. 130. John, C., et al., Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse. Front Endocrinol (Lausanne), 2018. 9: p. 732. 131. Balwierz, A., et al., Angiogenesis in the New Zealand obese mouse model fed with high fat diet. Lipids Health Dis, 2009. 8: p. 13. 132. Li, H., et al., Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide, 2002. 7(3): p. 149-64. 133. Leiter, E.H. and P.C. Reifsnyder, Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes. Diabetes, 2004. 53 Suppl 1: p. S4-11. 134. Joost, H.G. and A. Schurmann, The genetic basis of obesity-associated type 2 diabetes (diabesity) in polygenic mouse models. Mamm Genome, 2014. 25(9-10): p. 401-12. 135. Hink, U., et al., Mechanisms underlying endothelial dysfunction in diabetes mellitus: therapeutic implications. Treat Endocrinol, 2003. 2(5): p. 293-304. 136. Wakasaki, H., et al., Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A, 1997. 94(17): p. 9320-5. 137. Ishii, H., D. Koya, and G.L. King, Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med (Berl), 1998. 76(1): p. 21-31. 138. Hink, U., et al., Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res, 2001. 88(2): p. E14-22. 139. Viswambharan, H., et al., Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop. Circ Res, 2017. 120(5): p. 784-798. 140. Yu, Y., et al., Role of PYK2 in the development of obesity and insulin resistance. Biochem Biophys Res Commun, 2005. 334(4): p. 1085-91. 141. Wang, X.H., C.Y. Yan, and J.R. Liu, Hyperinsulinemia-induced KLF5 mediates endothelial angiogenic dysfunction in diabetic endothelial cells. J Mol Histol, 2019. 50(3): p. 239-251. 142. Matsui, A., et al., Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function. Circulation, 2007. 116(9): p. 1041-51. 143. Wei, H. and R.S. Vander Heide, Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes. Am J Physiol Heart Circ Physiol, 2008. 295(2): p. H561-8. 144. Han, S., et al., Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem, 2009. 284(19): p. 13193-201. 145. Lev, S., et al., Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature, 1995. 376(6543): p. 737-45. 146. Astier, A., et al., The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after beta1-integrin stimulation in B cells and binds to p130cas. J Biol Chem, 1997. 272(1): p. 228-32. 147. Dikic, I., et al., A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature, 1996. 383(6600): p. 547-50. 148. Okigaki, M., et al., Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci U S A, 2003. 100(19): p. 10740-5. 149. Ottosson-Seeberger, A., et al., Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans. Acta Physiol Scand, 1997. 161(2): p. 211-20. 150. Park, J.G., et al., PYK2 as a mediator of endothelin-1/G alpha 11 signaling to GLUT4 glucose transporters. J Biol Chem, 2001. 276(51): p. 47751-4. 151. Sajan, M.P., et al., Sorbitol activates atypical protein kinase C and GLUT4 glucose transporter translocation/glucose transport through proline-rich tyrosine kinase-2, the extracellular signal-regulated kinase pathway and phospholipase D. Biochem J, 2002. 362(Pt 3): p. 665-74. 152. Ishibashi, K.I., et al., Chronic endothelin-1 treatment leads to heterologous desensitization of insulin signaling in 3T3-L1 adipocytes. J Clin Invest, 2001. 107(9): p. 1193-202. 153. Wilkes, J.J., A. Hevener, and J. Olefsky, Chronic endothelin-1 treatment leads to insulin resistance in vivo. Diabetes, 2003. 52(8): p. 1904-9. 154. Schneider, J.G., et al., Elevated plasma endothelin-1 levels in diabetes mellitus. Am J Hypertens, 2002. 15(11): p. 967-72. 155. Rocha, N.G., et al., Metabolic syndrome and endothelin-1 mediated vasoconstrictor tone in overweight/obese adults. Metabolism, 2014. 63(7): p. 951-6. 156. Xue, M., et al., Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes, 2008. 57(10): p. 2809-17. 157. Pereira, A., et al., The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes. Sci Rep, 2017. 7(1): p. 14357. 158. Bielschowsky, M. and C.M. Goodall, Origin of inbred NZ mouse strains. Cancer Res, 1970. 30(3): p. 834-6. 159. Mestas, J. and C.C. Hughes, Of mice and not men: differences between mouse and human immunology. J Immunol, 2004. 172(5): p. 2731-8. 160. Seok, J., et al., Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A, 2013. 110(9): p. 3507-12. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | 03/2015-09/2020 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 26.10.2020 | |||||||
| Dateien geändert am: | 26.10.2020 | |||||||
| Promotionsantrag am: | 17.02.2020 | |||||||
| Datum der Promotion: | 23.09.2020 |
