INCREASED APOLIPOPROTEIN-E AND C-FMS GENE-EXPRESSION WITHOUT ELEVATEDINTERLEUKIN-1 OR INTERLEUKIN-6 MESSENGER-RNA LEVELS INDICATES SELECTIVE ACTIVATION OF MACROPHAGE FUNCTIONS IN ADVANCED HUMAN ATHEROMA

Cells found within atherosclerotic lesions can produce in culture prot ein mediators that may participate in atherogenesis. To test whether h uman atheromata actually contain transcripts for certain of these gene s, we compared levels of mRNAs in carotid or coronary atheromata and i n nonatherosclerotic human vessels by polymerase chain reaction (PCR) amplification of cDNAs reverse-transcribed from RNA. We measured PCR p roducts (generated during exponential amplification) by incorporation of P-32-labeled primers. Levels of interleukin 1-alpha, 1-beta, or 6 m RNAs in plaques and controls did not differ. Compared to uninvolved ve ssels, plaques did contain higher levels of mRNA encoding platelet-der ived growth factor A chain (42 +/- 24 vs. 12 +/- 10 fmol of product; m ean +/- SD; n = 8 and 8, respectively; P = 0.007) and B chain (41 +/- 36 vs. 4 +/- 3 fmol of product, n = 14 and 6, respectively; P = 0.024) . Atherosclerotic lesions consistently had much higher levels of apoli poprotein E (apoE) mRNA than did control vessels (131 +/- 71 vs. 5 +/- 3 fmol of product; n = 12 and 10, respectively; P < 0.001). Direct RN A blot analyses confirmed elevated levels of apoE mRNA in plaque extra cts. To test whether mononuclear phagocytes might be a source of the a poE mRNA, we studied a selective marker for cells of the monocytic lin eage, the c-fms protooncogene, which encodes the receptor for macropha ge colony-stimulating factor. Plaques also contained elevated levels o f c-fms mRNA (30 +/- 17 vs. 5 +/- 3 fmol of product; n = 10 and 7, res pectively; P = 0.002). Immunohistochemical colocalization demonstrated apoE protein in association with macrophages in plaques, whereas nona therosclerotic vessels showed no immunoreactive apoE. ApoE produced lo cally in atheroma might modulate the functions of lesional T cells or promote "reverse cholesterol transport" by associating with high densi ty lipoprotein particles, thus targeting them for peripheral uptake. M acrophages within the advanced human atheroma appear to exhibit a sele ctive program of activation as they express high levels of apoE, where as overall levels of interleukin 1 or 6 mRNAs in plaques are not eleva ted.