CONTENTS Introduction

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CONTENTS

Introduction

1. A FRIENDLY GLOSSARY OF RECURRING TERMS 5

1.1 Nuclear factor-kappa B (NFkB) ₅

1.2 Cytokines 6

1.3 Tumor necrosis factor alpha (TNF-α) 6

1.4 CD40 Ligand (L) 7

1.5 Transforming growth factor beta (TGF-β)1 ₈

1.6 Chemokines 8

1.7 C Reactive Protein (CRP) ₁₀ 1.8 Peroxisome proliferator-activated receptor(PPAR)s 10 1.9 Adhesion molecules 11 1.10 Matrix metalloproteinase(MMP)s 11

1.11 Adiponectin 12

1.12 Plasminogen Activator Inhibitor(PAI)-1 12 1.13 ROS as markers of oxidative stress and endothelial dysfunction 13

2. AN OVERVIEW OF INFLAMMATION IN ATHEROSCLEROSIS

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2.1 Atherosclerotic process 14 2.2 Renin Angiotensin System (RAS) 16 2.3 Angiotensin II Receptor Blocker(ARB)s 17

3. THE PRO-INFLAMMATORY ROLE OF ANGIOTENSIN II 21

3.1 Vascular permeability 21 3.2 Leukocytes intima infiltration 21 3.3 Tissue remodelling 22 3.4 Pro-oxidant role of angiotensin II 22

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4. THE ANTI-INFLAMMATORY EFFECT OF ARBS ₂₄

4.1 Candesartan (CAN) ₂₄ 4.2 Eprosartan (EPR) 26 4.3 Irbesartan (IRB) 26 4.4 Losartan (LOS) 27 4.5 Olmesartan (OLM) 29 4.6 Telmisartan (TEL) 29 4.7 Valsartan (VAL) 31 5. SPECIFIC BACKGROUND 32

Aim

Materials and Methods

6. EXPERIMENTAL METHODS 34

6.1 Endothelial cell preparation ₃₄ 6.2 Endothelial cell culture 34 6.3 Preparation of Retinal Derived Growth Factor (RDGF) 35 6.4 HUVEC characterization performed by Flow Cytometry 35

6.5 Drugs 36 6.6 ELISA 36 6.7 MTT assay 37 6.8 Comet assay 38 6.9 TOSC assay 39 7. EXPERIMENTAL DESIGN 40

7.1 TNF-α induced CAM expression 40 7.2 Pharmacological PPAR-γ manipulation 40 7.3 AII-mediated cell damage and effect of AT1R blockade 41 7.4 Hydrogen peroxide induced cell damage 41 7.5 Effect of TEL on in vitro TOSC 41

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8. DATA PROCESSING AND STATISTICS 42

Results

9. RESULTS 43

9.1 TNF-α induced CAM expression 43 9.2 Pharmacological PPAR-γ manipulation 47 9.3 AII-mediated cell damage and effect of AT1R blockade 48

9.4 H2O2-induced cell damage and effect of AT1R 49

9.5 The effect of TEL on in vitro TOSC 50

Discussion

Conclusion

Abbreviation

References

Appendix

10.2 SPECIFIC AIM AND INNOVATIVE ASPECTS 87

10.3 METHODS ₈₈

10.4 REASEARCH ACHIEVEMENTS 91 10.5 SUMMARY AND CONCLUSIONS 100