We propose that iron plays a critical role in adverse processes of importance in vascular and myocardial injury. Iron-mediated redox signaling may regulate growth factors and cell cycle progression leading to restenosis after vascular injury. Excessive iron overload leads to cardiac dysfunction. To study these issues we will employ a novel lipid-soluble iron chelator that rapidly enters cells and is far more effective in preventing iron-mediated reactions than chelators available heretofore. In AIM 1 we will study, in cultured human vascular smooth muscle and endothelial cells, the role of iron-mediated redox signaling on transcriptional activation of nuclear factor-kappa B, activator protein-1 and hypoxia-inducible factor (HIF), and signaling through protein kinase C. It is postulated that iron chelation, through interruption of these pathways, blocks cell cycle progression from G0/G1 to S phase of the cell cycle. We will also test whether HIF-mediated vascular endothelial growth factor expression has important effects on endothelial growth and function in cultured cells and a porcine vascular injury model. In AIM 2 we will study myocardial dysfunction due to iron overload in mice. Based on the hypothesis that iron overload induces mitochondrial injury from altered redox signaling or release of toxic levels of oxygen free radicals, alterations in specific targets, including cardiolipin, frataxin, manganese superoxide dismutase and heat shock proteins, will be examined. Because of the limitations of currently available iron chelators, we will study whether myocardial injury due to iron overload can be prevented by parenteral or oral administration of exochelin. Exochelin in desferri-form will be administered with or without concomitant use of an L-channel calcium blocker, which prevents myocyte uptake of non-transferrin-bound iron. In Aim 3 we will test the hypothesis that the lipid-solubility of exochelins accounts for their potency as anti-proliferative and cardio-protective agents because of site-specific iron chelation in the lipid portions of the cell membrane. Completion of these studies will greatly enhance our knowledge of the cardiovascular pathophysiology of iron-mediated redox reactions and evaluate the potential usefulness of a unique iron chelator, exochelin, for preventing vascular or myocardial injury through this mechanism.

R01HL055291

1996-02-01

2008-01-31