HEME AND THE VASCULATURE - AN OXIDATIVE HAZARD THAT INDUCES ANTIOXIDANT DEFENSES IN THE ENDOTHELIUM

Heme proteins transport oxygen and facilitate redox reactions. Heme, h owever, may be dangerous, especially when free in biologic systems. Fo r example, iron released from hemoglobin-derived heme can catalyze oxi dative injury to neuronal cell membranes and may be a factor in post-t raumatic damage to the central nervous system. We have shown that heme catalyzes the oxidation of low density lipoproteins which can damage vascular endothelial cells. The endothelium is susceptible to damage b y oxidants generated by activated phagocytes, and this has been invoke d as an important mechanism in a number of pathologies including the A dulte Respiratory Distress Syndrome (ARDS), acute tubular necrosis, re perfusion injury and atherosclerosis, Because of its highly hydrophobi c nature, heme readily intercalates into endothelia membranes and pote ntiates oxidant-mediated damage. This injury is dependent on the iron content of heme and is completely blocked when concomitant hemopexin i s added. Ferrohemoglobin, when added to cultured endothelial cells, is without deleterious effects, but if oxidized to ferrihemoglobin (meth emoglobin), it greatly amplifies oxidant damage, Methemoglobin, but no t ferrohemoglobin, releases its hemes which can then be incorporated i nto endothelial cells. Cultured endothelial cells, when exposed to met hemoglobin but not ferrohemoglobin, cytochrome c or metmyoglobin, pote ntiate this oxidant injury. Stabilization of the methemoglobin by cyan ide, haptoglobin or capture of the heme by hemopexin abrogates this ef fect. Paradoxically, more prolonged exposure of endothelium to heme or methemoglobin renders them remarkably resistant to oxidant challenge. Endothelium defends itself from heme by induction of the heme degradi ng enzyme heme oxygenase and the concomitant production of large amoun ts of the iron binding protein ferritin. The ferritin content of endot helial cells is inversely proportional to their susceptibility to oxid ant damage under a wide range of experimental conditions. We conclude that, acutely, delivery of free heme to the vasculature is hazardous b y sensitizing endothelial cells to oxidant damage while chronic exposu re upregulates their defense of heme oxygenase and ferritin.