Although much is known about the pathology of pulmonary hypertension, only limited information is available regarding pharmacologically-relevant signal transduction pathways. One important transduction pathway involves the polyamines, a family of low molecular weight organic cations that are essential for DNA, RNA, and protein synthesis. Because changes in lung cell polyamine contents may comprise a unified pathway through which diverse stimuli affect hypertensive pulmonary vascular remodeling, mechanisms regulating cellular polyamine contents may offer unique opportunities for pharmacologic intervention. Traditional concepts of polyamine regulation emphasize the role of de novo polyamine synthesis in governing changes in lung structure and function. In marked contrast, however, chronic hypoxic pulmonary hypertension is accompanied by decreased lung polyamine synthesis despite increases in polyamine contents. Current evidence supports the working hypothesis that increases in polyamine transport and attendant polyamine interconversion underlie adjustments in specific polyamine pools required for cell responses in hypoxic pulmonary vascular remodeling. Integrated experiments in cultured rat pulmonary arterial cells and intact rats will:
Aim 1 : Define the importance of polyamine transport and interconversion in terms of their roles in regulating specific polyamine pools in hypoxic pulmonary vascular endothelial and smooth muscle cells;
Aim 2 : Test the hypothesis that newly-transported polyamines are vectored into the nucleus and mitochondria where they subserve specific roles in the adaptive response to hypoxia;
Aim 3 : Determine the position of augmented polyamine transport in hypoxic signal transduction in terms of whether it is a cause or consequence of hypoxia-induced changes in cell calcium disposition, protein kinase C activation, and accumulation of specific transactivating factors; and, Aim 4: Resolve the practical issue of whether blockade of polyamine uptake or interconversion with novel inhibitors prevents development of hypoxic pulmonary vascular remodeling in intact rats. These experiments will generate unique insight into the mechanisms by which polyamines are regulated in hypoxic pulmonary vascular cells and provide the first direct test of the hypothesis that polyamine transport and interconversion are relevant pharmacologic targets in pulmonary hypertension. Such observations will add a new dimension to understanding the pharmacologic utility of these polyamine regulatory pathways in numerous disorders characterized by dysregulated cell proliferation and differentiation, including other cardiovascular diseases and neoplasia.
