ANTIPROLIFERATIVE GENE BTG1 IS HIGHLY EXPRESSED IN APOPTOTIC CELLS INMACROPHAGE-RICH AREAS OF ADVANCED LESIONS IN WATANABE HERITABLE HYPERLIPIDEMIC RABBIT AND HUMAN

In the present study, the expression and potential role of the highly conserved antiproliferative gene BTG1 in the process of apoptosis as i t occurs in atherosclerotic lesions was examined. In situ hybridizatio n and immunodetection studies demonstrated that BTG1 localized to spec ific macrophage-rich regions of lesions in both Watanabe heritable hyp erlipidemic rabbits and humans. In addition, the spatial distribution of BTG1 mRNA was shown to colocalize not only with macrophage-rich reg ions but also to cells that exhibited changes consistent with apoptosi s, such as DNA fragmentation and nuclear condensation. In vitro studie s demonstrated that forced overexpression of BTG1 induced a S-fold inc rease in apoptosis in NIH/3T3 cells. Furthermore, significantly increa sed expression of BTG1 mRNA resulted from lipid loading of human monoc yte-derived macrophages in vitro. The process of increasing lipid cont ent in macrophages is frequently associated with decreased macrophage viability. Taken together, these data underscore a potentially importa nt role for BTG1 in regulating the cellularity of advanced atheroscler otic lesions.