Abstract

The long range objective of this study is to examine the effects of endothelial cell membrane lipid modification on the fibrinolytic activity of the vascular endothelium and extracellular matrix (ECM) and their potential modulation by two potent endothelial cell mitogens with angiogenic properties, basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta). Intricate relationships exist among endothelial cells, fibrinolytic molecules (tissue plasminogen activator (t-PA)) and its inhibitor plasminogen activator inhibitor-1 (PAI- 1), and angiogenic mitogens that can regulate the fibrinolytic activity of the vasculature. Cellular cholesterol and saturated fatty acid enrichment as well as oxidized low density lipoprotein (LDL) have been demonstrated to induce dysfunction of endothelium in the pathogenesis of atherosclerosis. This project will test the hypothesis that endothelial cell membrane lipid modification will modulate fibrinolytic responses to angiogenic mitogens and the net fibrinolytic properties of the endothelium and its ECM.
The specific aims can be summarized as follows: 1. To investigate the effects of lipid modification of the endothelium on t-PA and PAI-1 activity, antigen levels, and mRNA levels; 2. To examine the effects of endothelial cell lipid modification on modulation of t-PA and PAI-1 protein secretion and regulation by bFGF and TGF-beta; 3. To characterize the effects of endothelial cell lipid modification on PAI-1 content of the ECM and its modulation by bFGF and TGF-beta; and 4. To study the effects of endothelial cell lipid modification on endothelial t-PA receptor synthesis and membrane availability and their potential modulation by bFGF and TGF-beta. Consequently, these studies should contribute to our knowledge of the regulation of the endothelial fibrinolytic system by lipid modification and mitogens, thereby elucidating the role for these important factors in the pathogenesis of atherosclerosis and thrombosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
1K11HL002578-01
Application #
3087812
Study Section
Research Manpower Review Committee (MR)
Project Start
1991-07-01
Project End
1996-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Simon, A D; Yazdani, S; Wang, W et al. (2001) Elevated plasma levels of interleukin-2 and soluble IL-2 receptor in ischemic heart disease. Clin Cardiol 24:253-6
Yazdani, S; Simon, A D; Vidhun, R et al. (1998) Inflammatory profile in unstable angina versus stable angina in patients undergoing percutaneous interventions. Am Heart J 136:357-61
Yazdani, S; Simon, A D; Kovar, L et al. (1997) Percutaneous interventions alter the hemostatic profile of patients with unstable versus stable angina. J Am Coll Cardiol 30:1284-7
Wang, W; Chen, H J; Warshofsky, M et al. (1997) Effects of S-dC28 on vascular smooth muscle cell adhesion and plasminogen activator production. Antisense Nucleic Acid Drug Dev 7:101-7
Wang, W; Chen, H J; Schwartz, A et al. (1997) Inhibitory nonsequence-specific effects of cytidine homopolymers on in vivo neointimal formation. Antisense Nucleic Acid Drug Dev 7:559-66
Warshofsky, M K; Wasserman, H S; Wang, W et al. (1997) Plasma levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are correlated with the presence of transplant coronary artery disease in cardiac transplant recipients. Am J Cardiol 80:145-9
Wang, W; Chen, H J; Schwartz, A et al. (1997) T cell lymphokines modulate bFGF-induced smooth muscle cell fibrinolysis and migration. Am J Physiol 272:C392-8
Wang, W; Chen, H J; Schwartz, A et al. (1996) Sequence-independent inhibition of in vitro vascular smooth muscle cell proliferation, migration, and in vivo neointimal formation by phosphorothioate oligodeoxynucleotides. J Clin Invest 98:443-50
Wang, W; Chen, H J; Giedd, K N et al. (1995) T-cell lymphokines, interleukin-4 and gamma interferon, modulate the induction of vascular smooth muscle cell tissue plasminogen activator and migration by serum and platelet-derived growth factor. Circ Res 77:1095-106
Rabbani, L E; Loscalzo, J (1994) Recent observations on the role of hemostatic determinants in the development of the atherothrombotic plaque. Atherosclerosis 105:1-7

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