First 11 pages of thesis. - OPUS - Universität Würzburg

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the survival rate, as apoE/nNOS dko mice had a 30% increased mortality compared to apoE ko controls. However, the exact mechanism by which nNOS acts as an anti-atherosclerotic enzyme is still not clear. It was speculated that nNOS localized towards to the lumen of the vessel might decrease leukocyte and platelet adhesion while nNOS expressed in the adventitia might inhibit smooth muscle cell proliferation 168 . Since nNOS also uncouples under conditions of substrate deficiency, the role of nNOS derived superoxide and nitric oxide in the formation of atherosclerosis still has to be defined. 1.6.3 Role of iNOS in cardiovascular diseases Under normal physiological conditions, iNOS is unlikely to have any functional role in the cardiovascular system due to its low (or absent) expression. However, a large number of reports are available which provide evidence for the expression of iNOS under pathophysiological conditions, both in humans as well as in animal models. In this respect, iNOS expression is detected in atherosclerosis, following balloon injury and restenosis, in cardiomyopathy, sepsis, transplant rejection and a variety of disorders associated with acute and chronic inflammation. Under normal physiological conditions iNOS expression has important anti microbial and anti tumor activities since it is capable of generating high cytotoxic concentration of nitric oxide. In chronic inflammation, however, the production of high cytotoxic nitric oxide and superoxide production by the enzyme may become detrimental. LPS injection was shown to increase leukocyte rolling and adhesion to post capillary venules of iNOS knockout (iNOS ko) mice suggesting that iNOS induction can act as a negative regulator of leukocyte trafficking in the microcirculation 169 . - 32 -
Transient gene transfer mediated expression of iNOS decreases smooth muscle cell proliferation and prevents neointima formation following balloon angioplasty in rats and pigs 170 . The same authors reported that iNOS gene transfer protects aortic allografts from developing allograft arteriosclerosis 171 . In mice, iNOS protects from developing transplant arteriosclerosis by inhibiting neointimal smooth muscle accumulation 172 . Another recent study showed that iNOS prevents vein graft arteriosclerosis by inhibiting vascular smooth muscle cell proliferation 173 and neointimal hyperplasia 174 . In vitro, iNOS ko mice show an improved cardiac reserve following myocardial infarction which was thought to be necessary to the reduction in oxidative stress seen in this model 175 . Genetic deletion of iNOS gene also led to partial protection against acute cardiac mechanical dysfunction mediated by pro-inflammatory cytokines 176 . The expression of iNOS is considered to be responsible for impairment of eNOS derived nitric oxide production in vessels treated with inflammatory mediators 177 . Further studies suggest that iNOS plays an important role in the impairment of endothelium dependent vascular relaxation, which may occur in part by limiting cofactor availability (BH4) and subsequent eNOS uncoupling 178 . The expression of iNOS by macrophages and smooth muscle cells in atherosclerotic lesions has been taken as evidence for its detrimental role in atherosclerosis, due to formation of peroxynitrite 179 . We and others have shown that genetic deletion of iNOS resulted in a significant reduction of lesion formation in apoE ko mice, documenting the proatherogenic potential of iNOS 180, 181 . Our results were reconfirmed by Hayashi et al. who showed that selective pharmacological inhibition of iNOS results in retardation of atherosclerosis in rabbits 182 . - 33 -
Page 1 and 2: Insight into oxidative stress media
Page 3 and 4: Eidesstattliche Erklärungen Hiermi
Page 6 and 7: Acknowledgements First and foremost
Page 8 and 9: “Research is to see what everybod
Page 10 and 11: Chapter 2 37 2.0 Materials and Meth
Page 12 and 13: Summary and Hypothesis 76 Zusammenf
Page 14 and 15: 1.0 Introduction Atherosclerosis, t
Page 16 and 17: which contribute to the lipid rich
Page 18 and 19: 1.2 Risk Factors Atherosclerosis ha
Page 20 and 21: 1.2.2 Environmental factors 1. High
Page 22 and 23: 1.3 Oxidative Stress Oxidative stre
Page 24 and 25: peroxynitrite 38 which by itself ca
Page 26 and 27: Pharmacological inhibition of nitri
Page 28 and 29: 1.4 The nitric oxide pathway in ath
Page 30 and 31: of NADPH, FAD and FMN, whereas the
Page 32 and 33: isoforms to the regulatory and targ
Page 34 and 35: perinuclear/golgi region within the
Page 36 and 37: nNOS interacts with several protein
Page 38 and 39: iNOS expression is regulated transc
Page 40 and 41: transport pathway and is an essenti
Page 42 and 43: Interestingly, BH4 supplementation
Page 46 and 47: The seemingly opposing effects of i
Page 48 and 49: The purpose of the study presented
Page 50 and 51: 2.0 Materials and Methods 2.1 Mater
Page 52 and 53: Reagents Source For Immunohistochem
Page 54 and 55: Others Reagents Source Pegulated Su
Page 56 and 57: 2.2 Methods 2.2.1 Detection of free
Page 58 and 59: 2.2.1.2 Principle of ESR ESR spectr
Page 60 and 61: spectra 190 . Addition of exogenous
Page 62 and 63: ings were prepared as mentioned abo
Page 64 and 65: X-band EMX spectroscope (Bruker Bio
Page 66 and 67: minutes. At last sections were wash
Page 68 and 69: 3.0 Results 3.1 eNOS is a significa
Page 70 and 71: 3.2 eNOS deletion decreases vascula
Page 72 and 73: 3.3 nNOS contributes little to vasc
Page 74 and 75: 3.5 iNOS contributes significantly
Page 76 and 77: Figure 13. Determination of iNOS de
Page 78 and 79: 3.8 iNOS deletion influences NADPH
Page 80 and 81: 4.0 Discussion 4.1 eNOS is a major
Page 82 and 83: in our apoE/eNOS dko model, these a
Page 84 and 85: under conditions of substrate or co
Page 86 and 87: vessels with the iNOS specific inhi
Page 88 and 89: Summary and Hypothesis The principl
Page 90 and 91: Zusammenfassung und Hypothese Stick
Page 92 and 93: Bibliography 1. Gimbrone MA, Jr. Va
Page 94 and 95:
xanthine oxidase contributes to vas
Page 96 and 97:
expression of adhesion molecules an
Page 98 and 99:
transforming growth factor-beta 1.
Page 100 and 101:
generation from neuronal nitric oxi
Page 102 and 103:
148. Lee PC, Wang ZL, Qian S, Watki
Page 104 and 105:
174. Mayr U, Zou Y, Zhang Z, Dietri
Page 106 and 107:
implications in intracellular fluor
Page 108 and 109:
Definitions Thesaurus • Allograft
Page 110 and 111:
• Claudication refers to leg pain
Page 112 and 113:
cases per year in the US. It is a n
Page 114 and 115:
Curriculum Curriculum vitae vitae N
Page 116 and 117:
presentation at the 37 th Annual co
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First 11 pages of thesis. - OPUS - Universität Würzburg

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