150-KD OXYGEN-REGULATED PROTEIN IS EXPRESSED IN HUMAN ATHEROSCLEROTICPLAQUES AND ALLOWS MONONUCLEAR PHAGOCYTES TO WITHSTAND CELLULAR STRESS ON EXPOSURE TO HYPOXIA AND MODIFIED LOW-DENSITY-LIPOPROTEIN

The 150-kD oxygen-regulated protein (ORP150) was initially characteriz ed based on its selective expression in astrocytes subjected to oxygen deprivation (Kuwabara, K,, M. Matsumoto, J, Ikeda, O, Hori, S. Ogawa, Y. Maeda, K, Kitagawa, N. Imuta, K, Kinoshita, D.M. Stern, et al, 199 6, J, Biol. Chem. 279:5025-5032), We have found that exposure of cultu red human aortic smooth muscle cells and mononuclear phagocytes (MPs) to hypoxia (pO(2) similar to 12-14 torr) induces ORP150 transcripts an d production of the antigen, whereas incubation with either hydrogen p eroxide, sodium arsenite, heat shock, or 2-deoxyglucose was without ef fect, Tissue extracts prepared from human atherosclerotic lesions demo nstrated expression of ORP150 mRNA and antigen, vs lack of ORP150 in s amples from nonatherosclerotic areas, In situ hybridization using ORP1 50 riboprobes showed the mRNA to be predominately present in macrophag es in atherosclerotic plaques, Furthermore, autoantibody to ORP150 was demonstrated in the serum of patients with severe atherosclerosis, co nsistent with inducible in vivo expression of ORP150. Introduction of antisense oligonucleotide for ORP150 selectively diminished hypoxia-me diated induction of ORP150 antigen and reduced the viability of hypoxi c MPs, especially in the presence of modified (oxidized/acetylated) LD L. In support of a role for ORP150 in the MPs' response to the microen vironment of an atheroma, the presence of oxidized LDL enhanced by sim ilar to 10-fold ORP150 expression in hypoxic cultures. These data indi cate that cells of the atherosclerotic vessel wall express ORP150 as p art of a protective mechanism, potentially triggered by local hypoxia/ hypoxemia and augmented by modified lipoproteins. The presence of anti body to ORP150 in sera of patients with severe atherosclerosis emphasi zes the possibility that ORP150 may be a marker of vascular pathology.