INDUCTION OF HEME OXYGENASE-1 INHIBITS THE MONOCYTE TRANSMIGRATION INDUCED BY MILDLY OXIDIZED LDL

Heme catabolic processes produce the antioxidants biliverdin and bilir ubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether he me catabolism promotes or inhibits inflammatory processes, including a therosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rat e-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible rol e of HO in early atherosclerosis. Heme oxygenase-l (HO-1), the inducib le isoform of HO, was highly induced by mildly oxidized LDL, and augme nted induction was observed with hemin pretreatment. This augmented HO -1 induction resulted in the reduction of monocyte chemotaxis in respo nse to LDL oxidation. Conversely, inhibition of HO by a specific inhib itor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreat ment with biliverdin or bilirubin, the products of HO, reduced chemota xis. Oxidized phospholipids in the mildly oxidized LDL appear to be re sponsible for HO-I induction, since oxidized but not native arachidoni c acid-containing phospholipids also induced HO-1. These results sugge st that HO-I induced by mildly oxidized LDL may protect against the in duction of inflammatory responses in artery wall cells through the pro duction of the antioxidants biliverdin and bilirubin.