IRON MEDIATED CARDIOVASCULAR INJURY

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Iron plays a critical role in two processes of great importance in cardiovascular diseases: vascular smooth muscle proliferation and reperfusion injury. We have isolated, synthesized and completed highly promising pilot studies on a family of iron chelators,exochelins 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 damage by reactive oxygen species to cultured cardiac myocytes, reperfusion injury in isolated rabbit hearts and proliferation of cultured human vascular smooth muscle cells (VSMCs). We propose to elucidate the molecular mechanisms by which iron chelation with lipid-soluble exochelins prevent VSMC growth. In cultured human 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, particularly p21. We will examine the uptake and intracellular distribution of exochelins and the extent to which they influence VSMC growth through interruption of redox signaling. In separate studies we will assess whether exochelins given intramurally or intracoronary will prevent coronary artery restenosis due to VSMC proliferation following angioplasty in a porcine model. We will also assess the effects of desferri-exochelins given during reperfusion on myocardial infarct size, normalized for volume at risk and collateral blood flow, in a rigorous canine model involving 90 min of coronary occlusion and 48 hours of reperfusion. Finally we will examine whether desferri-exochelins prevent apoptosis, a genetically programmed mechanism of cell death that has been associated with reperfusion injury. We believe that exochelins have extraordinary potential for prevention of vascular and reperfusion injury, and are uniquely suitable for understanding the role of iron in these processes. This project would offer important mechanistic information at the molecular level and critical potential proof of principle for important therapeutic applications. We submit that our considerable progress to date and our unique familiarity with exochelins establishes that we have the capabilities to complete these exciting studies.