Abdominal aortic aneurysms (AAAs) are a common degenerative disease with life-threatening implications. While the pathophysiologic events underlying the development of AAA are still poorly understood, they clearly involve degenerative remodeling of aortic wall connective tissue. Recent studies have implicated three processes in this pathologic pattern of remodeling: (1) impaired repair of fibrillar extracellular matrix proteins, (2) chronic mononuclear inflammation, and (3) excessive local production of matrix-degrading proteinases. The purpose of this collaborative research program is to gain better understanding of the molecular mechanisms regulating these three processes. First, Drs. William C. Parks and J. Michael Shipley will examine the molecular factors that appear to limit the effective production of elastic fibers in the aneurysm wall environment. Using tissues obtained from human and experimental AAA and aneurysm-derived vascular smooth muscle cells in culture, they will specifically evaluate the molecular pathways controlling tropoelastin gene expression and tropoelastin mRNA stability, as well as the regulation of additional gene products involved in elastic fiber assembly, such as fibrillin-1 and latent TGF-beta binding protein-2. Second, Dr. Jay Heinecke will examine protein oxidation associated with chronic inflammation as an important pathway of tissue destruction. Using novel methods to detect and measure the contributions of different oxidative pathways to protein modification, he will determine the dominant oxidative pathways in human and experimental AAA, elucidate how protein oxidation serves to promote matrix metalloproteinase activity in aneurysm tissue, and examine how genetic manipulation affecting specific oxidative pathways might alter aneurysm development in a mouse model. Third, Dr. Robert W. Thompson will examine the regulated expression of three different interstitial collagenases, both in human AAA tissues from various stages of disease and in cultured SMC exposed to proinflammatory cytokines, phorbol ester and doxycycline. These studies will have a particular focus on collagenase-3 (MMP-13), providing new insight into the regulation of MMP-13 expression in vascular wall cells. Knowledge gained through these three closely-linked studies will help advance our understanding of the molecular pathophysiology of aortic aneurysms, potentially leading to new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064332-01
Application #
6051758
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Imamura, S; Kobayashi, J; Nakajima, K et al. (2008) A novel method for measuring human lipoprotein lipase and hepatic lipase activities in postheparin plasma. J Lipid Res 49:1431-7
Bartoli, Michel A; Parodi, Federico E; Chu, Jack et al. (2006) Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm. Ann Vasc Surg 20:228-36
Van Vickle-Chavez, Sarah J; Tung, William S; Absi, Tarek S et al. (2006) Temporal changes in mouse aortic wall gene expression during the development of elastase-induced abdominal aortic aneurysms. J Vasc Surg 43:1010-20
Curci, John A; Thompson, Robert W (2004) Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context? J Clin Invest 114:168-71
Buckley, Celine; Wyble, Charles W; Borhani, Martin et al. (2004) Accelerated enlargement of experimental abdominal aortic aneurysms in a mouse model of chronic cigarette smoke exposure. J Am Coll Surg 199:896-903
Absi, Tarek S; Sundt 3rd, Thoralf M; Tung, William S et al. (2003) Altered patterns of gene expression distinguishing ascending aortic aneurysms from abdominal aortic aneurysms: complementary DNA expression profiling in the molecular characterization of aortic disease. J Thorac Cardiovasc Surg 126:344-57; discission 357
Herbst, Karen L; Amory, John K; Brunzell, John D et al. (2003) Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk. Am J Physiol Endocrinol Metab 284:E1112-8
Steinmetz, Eric F; Buckley, Celine; Thompson, Robert W (2003) Prospects for the medical management of abdominal aortic aneurysms. Vasc Endovascular Surg 37:151-63
Hance, Kirk A; Tataria, Monika; Ziporin, Scott J et al. (2002) Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor. J Vasc Surg 35:254-61
Tung, W S; Lee, J K; Thompson, R W (2001) Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array. J Vasc Surg 34:143-50

Showing the most recent 10 out of 11 publications