Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

............................................................................................................................ V POPULÄRVETENSKAPLIG SAMMANFATTNING .................................................... VII LIST OF PUBLICATIONS .................................................................................................... 1 ABBREVIATIONS .................................................................................................................. 3 INTRODUCTION.................................................................................................................... 5 ANEURYSM ............................................................................................................................. 5 ABDOMINAL AORTIC ANEURYSM ............................................................................................. 6 Definition .................................................................................................................................................................... 6 Prevalence and risk factors .......................................................................................................................................... 6 Diagnosis of AAA ....................................................................................................................................................... 8 ANATOMY OF THE AORTA ........................................................................................................ 9 COMPONENTS OF THE AORTIC WALL...................................................................................... 10 Elastin........................................................................................................................................................................ 11 Collagen .................................................................................................................................................................... 11 Vascular smooth muscle cells ................................................................................................................................... 11 PATHOGENESIS OF AAA........................................................................................................ 12 CHRONIC INFLAMMATION AND IMMUNE RESPONSE IN AAA .................................................. 14 PROTEASES IN AAA .............................................................................................................. 15 TOLL-LIKE RECEPTORS .......................................................................................................... 17 Toll-like receptor signaling ....................................................................................................................................... 17 TLRs in animal models of aneurysm disease ............................................................................................................ 19 PLATELET-DERIVED GROWTH FACTOR................................................................................... 19 ADIPONECTIN – AN ADIPOKINE .............................................................................................. 20 INVOLVEMENT OF PERIVASCULAR ADIPOSE TISSUE IN VASCULAR INFLAMMATION ................ 22 SPHINGOLIPID METABOLITES – CERAMIDE AND SPHINGO-1-PHOSPHATE................................ 23 MEDICAL TREATMENT FOR AAA .......................................................................................... 24 AIMS ....................................................................................................................................... 27 METHODOLOGICAL CONSIDERATIONS .................................................................... 29 ANGIOTENSIN II INDUCED ABDOMINAL AORTIC ANEURYSM MODEL IN MICE ......................... 29 DETERMINATION OF MOUSE ABDOMINAL AORTIC DIAMETER ................................................ 32 ADENOVIRAL GENE TRANSFER .............................................................................................. 34 STUDY POPULATION .............................................................................................................. 35 Paper I and II ............................................................................................................................................................. 36 Paper IV .................................................................................................................................................................... 36 REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION .................................................. 36 PARAFFIN EMBEDDING AND SECTIONING ............................................................................... 37 IMMUNOHISTOCHEMISTRY .................................................................................................... 37 Avidin and biotin detection ....................................................................................................................................... 38 MACH II detection .................................................................................................................................................... 38 Quantification by immunohistochemistry ................................................................................................................. 38 MASSON ́S TRICHROME STAINING .......................................................................................... 39 VERHOEFF ́S VAN GIESON STAINING ..................................................................................... 39 PICRO-SIRIUS RED STAINING .................................................................................................. 40 TOLUIDINE BLUE ................................................................................................................... 41 STATISTICAL ANALYSIS ......................................................................................................... 42 RESULTS AND DISCUSSION ............................................................................................ 43 TRIF ADAPTOR SIGNALING IS IMPORTANT IN ABDOMINAL AORTIC ANEURYSM FORMATION (PAPER I) ............................................................................................................................... 43 IMATINIB TREATMENT ATTENUATES GROWTH AND INFLAMMATION OF ANGIOTENSIN IIINDUCED ABDOMINAL AORTIC ANEURYSM (PAPER II) ........................................................... 46 ADIPONECTIN INHIBITS ANGIOTENSIN II INDUCED ABDOMINAL AORTIC ANEURYSM FORMATION (PAPER III) ........................................................................................................ 50 INFLAMMATORY CELLS, CERAMIDES AND EXPRESSION OF PROTEASES IN PERIVASCULAR ADIPOSE TISSUE ADJACENT TO HUMAN ABDOMINAL AORTIC ANEURYSMS (PAPER IV) .......... 54 CONCLUDING REMARKS ................................................................................................ 57 ACKNOWLEDGEMENT ..................................................................................................... 61 REFERENCES ....................................................................................................................... 65