The lack of understanding of molecular mechanisms underlying abdominal aortic aneurysm (AAA) currently limits the prevention and treatment of this human disease. Previous studies by the applicants and others established profound inflammation associated with a predominantly lymphocytic infiltrate, the loss of extracellular matrix, and the paucity of smooth muscle cells as prominent morphologic characteristics of human AAA. Based on these and further preliminary studies presented here, the applicants propose a novel hypothesis regarding the inflammatory triggers and downstream effector mechanisms of extracellular matrix destruction yielding AAA. Specifically, we propose that the formation of human AAA is promoted by the expression of inflammatory triggers of the TH2 lymphocyte subset and/or the absence of TH1-associated cytokines, as well as the imbalance of downstream elastolytic, collagenolytic, or apoptotic effectors with their endogenous inhibitors.
In Specific Aim 1 we will test this hypothesis in vitro and in situ, phenotyping the leukocyte subpopulation(s) and characterizing expression of the respective upstream triggers (TH1/TH2 cytokines) as well as downstream elastolytic and collagenolytic (cathepsins, MMPs) as well as apoptotic (caspases, Fas/FasL) effectors, employing carefully characterized human AAA specimens. Studies determining the modulation of these downstream effectors by TH2 cytokines (particularly in the absence of TH1 typical cytokines) will elevate this aim to the functional level. The studies testing the novel propagated molecular mechanisms underlying AAA pathophysiology will be compared to those obtained in the predominantly TH1-driven aortic occlusive disease.
In Specific Aim 2 we will test this hypothesis in vivo in genetically altered mice. In a novel aortic transplant model, established by the applicants, we will test whether the systemic or local deficiency of distinct TH1/TH2 cytokines (IFNgamma, IL-4, or IL-10) as upstream triggers, or imbalance of downstream etastolytic/collagenolytic effectors with their endogenous inhibitors will yield aortic ectasia, a model of aneurysmal disease. In addition, these experiments will employ hypercholesterolemic compound mutant mice, combining a predominant TH1 or TH2 skewed immuneresponse or the systemic imbalance of elastolytic/collagenolytic activities with the predisposition to atherosclerotic disease (apoE deficient mice), to test whether modulations in defined inflammatory or proteolytic paradigms, respectively, affect AAA formation differently when exposed to an atherogenic background. Combined, the two Specific Aims will determine whether differential immune mediator-associated mechanisms triggering proteolytic and apoptotic effectors regulate the development of the two diametrically opposed expressions of aortic diseases-AAA and AOD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067249-03
Application #
6915048
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
2003-08-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$368,481
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Tang, Eva H C; Shvartz, Eugenia; Shimizu, Koichi et al. (2011) Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 31:261-9
Schulte, Stephanie; Sun, Jiusong; Libby, Peter et al. (2010) Cystatin C deficiency promotes inflammation in angiotensin II-induced abdominal aortic aneurisms in atherosclerotic mice. Am J Pathol 177:456-63
Shimizu, Koichi; Minami, Manabu; Shubiki, Rica et al. (2009) CC chemokine receptor-1 activates intimal smooth muscle-like cells in graft arterial disease. Circulation 120:1800-13
Deguchi, Jun-o; Huang, Hayden; Libby, Peter et al. (2009) Genetically engineered resistance for MMP collagenases promotes abdominal aortic aneurysm formation in mice infused with angiotensin II. Lab Invest 89:315-26
Shimizu, Koichi; Libby, Peter; Shubiki, Rica et al. (2008) Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection. Circulation 117:1997-2008
Noma, Kensuke; Rikitake, Yoshiyuki; Oyama, Naotsugu et al. (2008) ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest 118:1632-44
Sun, Jiusong; Sukhova, Galina K; Yang, Min et al. (2007) Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 117:3359-68
Isoda, Kikuo; Folco, Eduardo J; Shimizu, Koichi et al. (2007) AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL. Atherosclerosis 192:298-304
Kitamoto, Shiro; Sukhova, Galina K; Sun, Jiusong et al. (2007) Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115:2065-75
Sun, Jiusong; Sukhova, Galina K; Wolters, Paul J et al. (2007) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13:719-24

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