Immediately following PTCA, oxidant-producing inflammatory leukocytes accompany platelets into the injury site. The response shortly thereafter includes the proliferation of smooth muscle cells (SMC) which ceases in a matter of weeks and is accompanied by hypertrophy and enhanced connective tissue synthesis. Depending apparently on the magnitude and duration of multiple proliferative stimuli and the timing and strength of inhibitory signals, this proliferation of cells and growth of connective tissue may reach proportions which compromise the vessel lumen. Our hypothesis to explain these events includes the participation of low concentrations of oxidants (such as H2O2) and particular lipid oxidation products, as direct stimuli of SMC proliferation, adding to the proliferative effects of other growth factors present, such as platelet-derived growth factor (PDGF). Our hypothesis further contends that these lipid oxidation products suppress the production of transforming growth factor-type beta (TGFbeta1). We propose that the potent inhibitory action of TGFbeta1 on SMC proliferation ultimately signals the end of the proliferative response to PTCA and is responsible for the enhancement of connective tissue synthesis. We propose several lines of investigation to test this hypothesis.
In Aim 1 we propose measuring the gene expression and production of TGFbeta1 by proliferating vascular cells and the responsiveness of the cells to TGFbeta1. Three cell culture populations will be studied: (a) human aorta derived SMC, (b) cells grown from tissue obtained during atherectomy of human arteries recently treated by PTCA and (c) cells grown from restenosed arterial tissue obtained from a rabbit model of PTCA.
In Aim 2 we plan to characterize the proliferative stimulus of low levels of oxidants, lipid oxidation products and oxidized lipoproteins to human aortic SMC. In addition, we propose to examine the inhibitory effects of these agents on the gene expression and production of TGFbeta1 by cell populations that are putative sources of this potent inhibitor in the proliferating lesion, i.e., SMC, endothelial cells and monocyte-derived macrophages. Active oxidized lipid fractions will be purified by HPLC. Human atherectomy samples and restenotic rabbit lesions will be examined for lipid oxidation products.
In Aim 3 we propose testing in rabbits, the ability of lipophilic antioxidant pretreatment to alter the course of the proliferative response to PTCA.
|Ananyeva, N M; Tjurmin, A V; Berliner, J A et al. (1997) Oxidized LDL mediates the release of fibroblast growth factor-1. Arterioscler Thromb Vasc Biol 17:445-53|
|Penn, M S; Rangaswamy, S; Saidel, G M et al. (1997) Macromolecular transport in the arterial intima: comparison of chronic and acute injuries. Am J Physiol 272:H1560-70|
|Chai, Y C; Howe, P H; DiCorleto, P E et al. (1996) Oxidized low density lipoprotein and lysophosphatidylcholine stimulate cell cycle entry in vascular smooth muscle cells. Evidence for release of fibroblast growth factor-2. J Biol Chem 271:17791-7|
|Freeman, E J; Chisolm, G M; Ferrario, C M et al. (1996) Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. Hypertension 28:104-8|
|Freeman, E J; Chisolm, G M; Tallant, E A (1995) Role of calcium and protein kinase C in the activation of phospholipase D by angiotensin II in vascular smooth muscle cells. Arch Biochem Biophys 319:84-92|
|Lafont, A; Guzman, L A; Whitlow, P L et al. (1995) Restenosis after experimental angioplasty. Intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res 76:996-1002|
|Lafont, A M; Chai, Y C; Cornhill, J F et al. (1995) Effect of alpha-tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis. J Clin Invest 95:1018-25|
|Ehrenwald, E; Chisolm, G M; Fox, P L (1994) Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J Clin Invest 93:1493-501|
|Penn, M S; Saidel, G M; Chisolm, G M (1994) Relative significance of endothelium and internal elastic lamina in regulating the entry of macromolecules into arteries in vivo. Circ Res 74:74-82|
|Reddy, K B; Howe, P H (1993) Transforming growth factor beta 1-mediated inhibition of smooth muscle cell proliferation is associated with a late G1 cell cycle arrest. J Cell Physiol 156:48-55|
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