This proposal grew out of our recent discovery of unique gene expression profiles of coronary and mammary arteries. There is extensive and compelling evidence demonstrating that there are underlying differences in propensity of different arteries to develop atherosclerosis. However, the underlying molecular mechanisms for these differences are completely unexplored. We have generated reciprocal cDNA collections of representing mRNA specific to porcine coronary vs. porcine mammary arteries. Pleiotrophin (PTN) gene was found to be specifically expressed in the coronary artery. PTN is a multifunctional cytokine that has been expressed by tumors and has been implicated in tumorigenesis. However, the cardiovascular activity of PTN remains unknown. Since PTN exhibits activities that are relevant to vascular pathologies, this application is based on the hypothesis that expression of PTN in arterial wall contributes to vascular pathologies and vascular remodeling. This project will characterize the role of PTN in neointimal formation by using in vitro and animal model systems. We propose interrelated studies that are designed to identify the cellular mechanism mediated by PTN that contributes to vascular remodeling, to evaluate the efficacy of intervention reducing PTN gene expression and its receptor expression, and to explore the PTN gene-specific mechanism of neointimal thickening. By studying how PTN contributes to vascular remodeling and identify the underlying cellular and molecular mechanism that mediates activity of PTN in the vessel wall, this application promises to take an important new step toward understanding how specific gene play a part in the pathogenesis of vascular disorders.
Cardiovascular disease remains the leading cause of death in men and women in the United States;about 1.26 million Americans this year will have a new or recurrent heart attack resulting from atherothrombosis, indicating the need for new therapeutic approaches. We have recently identified a novel gene, PTN, which has biological activities that could make it an important player in cardiovascular disease. In this grant proposal, we aim to further define the role of PTN gene in vascular disease in an animal model and cultured cells with the hope that in the future, modifying PTN activity may emerge as a new therapeutic approach against vascular pathologies.