Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development.

Abstract

Signal transducer and activator of transcription 1 (Stat1) potently regulates gene expression after stimulation by certain cytokines involved in tumorigenesis and host defenses. The present study investigated a novel role for Stat1 in foam cell formation and atherosclerosis. Inhibition of Stat1 activity by a Stat1-specific DNA "decoy" oligomer transfected into differentiated human THP-1 cells, and deficiency of stat1 in mouse macrophages significantly inhibited foam cell formation assessed by lipid staining and cholesteryl ester accumulation compared with control cells. The mechanism of Stat1 regulation of foam cell formation was uniquely dependent on the scavenger receptor CD36. Blunted Stat1 activity and stat1 deficiency significantly decreased expression of CD36 but not of scavenger receptor-A compared with controls, as assessed by immunoblotting and flow cytometry. Deficiency of CD36 but not scavenger receptor-A in mouse macrophages removed any dependency of foam cell formation on Stat1. In an intraperitoneal model of foam cell formation in which foam cells form in vivo independently of the model ligands used in vitro, stat1 deficiency significantly inhibited foam cell formation and CD36 expression. Transplantation of bone marrow from apolipoprotein e-/- x stat1-/- mice into lethally irradiated, atherosclerosis-susceptible apolipoprotein e-/- recipients significantly reduced both en face aortic lesion coverage and aortic root lesions compared with recipients of bone marrow from genetically matched apolipoprotein e-/- mice. Stat1 regulates CD36 expression and foam cell formation in macrophages in vitro; the Stat1 regulation of foam cell formation requires CD36. The regulation of CD36 expression by Stat1 may be important in other pathophysiological CD36-dependent events. Stat1 deficiency reduces atherosclerosis in an apolipoprotein e-/- atherosclerosis-susceptible bone marrow transplantation model.