The overall, long-term objective of this project is to achieve further understanding of the mechanisms underlying growth regulation in the vascular wall. Injury and disease of the vascular wall is characterized, in large part, by proliferation of vascular smooth muscle (VSMC), leading to occlusion of the vessel lumen. Exogenous heparin and endogenous heparin sulfates inhibit VSMC proliferation seen following surgical procedures, e.g., bypasses, endarterectomies, heart transplantation, and vein grafts, and the latter suggesting a regulatory role for heparan sulfates in vascular growth control.
The specific aims of this project are twofold: firstly, to uncover the cellular and molecular mechanisms whereby heparin and its derivatives inhibit VSMC growth. To these ends, heparin's effects on the early events in the activation of VSMC by mitogens will be studied. These include effects of heparin on the binding of specific mitogens to their receptors, receptor phosphorylations, phosphorylation of tyrosine residues in proteins, expression and/or phosphorylation of specific mitogen-dependent proteins, activation of protein kinase C, phosphatidylinositol metabolism, activation of the Na+/H+ antiport, intracellular pH changes, and cell-cycle proto-oncogene expression effects will be studied at the transcription and post-transcriptional levels. The relationship of the gene effects to inhibition of growth will be evaluated. Late events such as effects of VSMC adhesion, the relationship of adhesion to cell division, and isolation and characterization of the adhesion molecules involved, will be studied. Secondly, the effects of heparin and heparin derivatives, particularly nonanticoagulant, antiproliferative derivatives will be evaluated in regard to accelerated atherosclerosis observed in a rat heart transplant model, and in experimental vein grafts. In both these frequently performed procedures, VSMC proliferation is a major clinical problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL017747-23
Application #
2430612
Study Section
Special Emphasis Panel (NSS)
Project Start
1979-06-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
23
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Fan, Wen-Hua; Karnovsky, Morris J (2002) Increased MMP-2 expression in connective tissue growth factor over-expression vascular smooth muscle cells. J Biol Chem 277:9800-5
Fan, W H; Karnovsky, M J (2000) Activation of protein kinase C inhibits the expression of connective tissue growth factor. Biochem Biophys Res Commun 275:312-21
Fan, W H; Pech, M; Karnovsky, M J (2000) Connective tissue growth factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro. Eur J Cell Biol 79:915-23
Edelman, E R; Nathan, A; Katada, M et al. (2000) Perivascular graft heparin delivery using biodegradable polymer wraps. Biomaterials 21:2279-86
San Antonio, J D; Verrecchio, A; Pukac, L A (1998) Heparin sensitive and resistant vascular smooth muscle cells: biology and role in restenosis. Connect Tissue Res 37:87-103
Pukac, L; Huangpu, J; Karnovsky, M J (1998) Platelet-derived growth factor-BB, insulin-like growth factor-I, and phorbol ester activate different signaling pathways for stimulation of vascular smooth muscle cell migration. Exp Cell Res 242:548-60
Pukac, L A; Carter, J E; Ottlinger, M E et al. (1997) Mechanisms of inhibition by heparin of PDGF stimulated MAP kinase activation in vascular smooth muscle cells. J Cell Physiol 172:69-78
Pukac, L A; Carter, J E; Morrison, K S et al. (1997) Enhancement of diaminobenzidine colorimetric signal in immunoblotting. Biotechniques 23:385-8
Rogers, C; Welt, F G; Karnovsky, M J et al. (1996) Monocyte recruitment and neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol 16:1312-8
Shin, Y T; Adams, D H; Wyner, L R et al. (1995) Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model. Transplantation 59:1647-53

Showing the most recent 10 out of 60 publications