LIPOPHILIC SIDEROPHORES MYCOBACTERIUM-TUBERCULOSIS PREVENT CARDIAC REPERFUSION INJURY

Reperfusion injury, which occurs upon the reintroduction of blood flow to an ischemic organ, is responsible for considerable damage in heart attacks and strokes. However, no treatment for reperfusion injury is currently available, A major cause of reperfusion injury is the iron-m ediated generation of hydroxyl radical (. OH). In this study we have e xplored the capacity of novel iron chelators called ''exochelins'' to prevent reperfusion injury. Exochelins, siderophores of Mycobacterium tuberculosis, are unique iron chelators because they are lipid soluble , and hence able to enter cells rapidly, In the iron-free state, exoch elins prevented . OH formation, Desferri-exochelins prevented oxidativ e injury to cultured cardiac myocytes, and did so more rapidly and eff ectively than the nonlipid soluble iron chelator deferoxamine, The cap acity of various desferri-exochelins to protect myocytes from oxidativ e injury varied directly with their solubility in lipid. Infused into isolated rabbit hearts during reperfusion after a period of ischemia, desferri-exochelins dramatically improved systolic and diastolic left ventricular function, preserved coronary flow, reduced release of the cardiac enzyme lactic dehydrogenase, and reduced myocardial concentrat ions of . OH metabolites, Thus, highly diffusible desferri-exochelins block injury caused by . OH production and have potential for the trea tment of reperfusion injury.