Iron plays a critical role in cardiovascular diseases: vascular smooth muscle proliferation and migration. We have isolated, synthesized and completed highly promising pilot studies on a family of iron chelators, exochenins secreted by Mycobacterium tuberculosis. They block redox reactions and are unique among chelators in that they are lipid soluble, a property that permits them to rapidly enter cells and be physiologically active at extremely low concentrations. In the desferri-form, exochelins prevent proliferation of cultured human vascular smooth muscle cells (VSMC). We propose to elucidate the molecular mechanism by which iron chelation with lipid soluble exochelins prevent VSMC growth. In cultured humans VSMCs, we will test the hypothesis that exochelins block progression through the cell cycle at both the G1 and S phases by inhibiting activity of cyclin-dependent kinases. We propose that this occurs through upregulation of inhibitory proteins. We will examine the uptake and intracellular distribution of exochelins in human VSMC.
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