Although much is known about the pathology of intimal hyperplasia (IH), little information is available regarding the cellular signaling mechanisms which coordinate cellular responses that lead to lesion formation. One important pathway may involve polyamines, a family of low molecular weight cations that are essential for mammalian DNA, RNA, and protein synthesis. The activity of ornithine decarboxylase (ODC), the initial and one of the rate-limiting enzymes for de novo polyamine synthesis, is known to increase after an arterial injury. Because arterial cell content of polyamines may be an end result of signal transduction by diverse stimuli (e.g. PDGF, basic FGF, TGFB, arterial wall shear stresses), mechanisms regulating cellular polyamine content may offer unique opportunities for pharmacologic intervention. For example, inhibition of ODC with alpha-difluromethylornithine (DFMO) has been shown to result in a significant decrease of intimal hyperplasia after an arterial deendothelialization injury. The proposed research will test key aspects of the working hypothesis that elevation of cellular polyamine production and/or transmembrane transport constitutes an obligatory biochemical link between vascular injury and arterial smooth muscle proliferation, which contributes to the development of intimal hyperplasia. To resolve this hypothesis, integrated studies carried out in intact, male Sprague-Dawley rats and cultured arterial smooth muscle cells will: 1) Delineate the relative contributions of polyamine synthesis versus transmembrane transport to the development of the IH lesion, and; 2) Define the molecular mechanisms regulating cellular polyamine content after arterial injury. This research will provide a rigorous evaluation of the role of polyamines in the signal transduction cascade, linking arterial injury to aspects of IH formation. In addition, the polyamine biosynthetic pathway may be identified as a pharmacologic target for intervention to inhibit the formation of IH.
| Toursarkissian, B; Endean, E D; Aziz, S M (1994) Characterization of polyamine transport in rat aortic smooth muscle cells. J Surg Res 57:401-7 |
