DIETARY GAMMA-LINOLENIC ACID MODULATES MACROPHAGE-VASCULAR SMOOTH-MUSCLE CELL-INTERACTIONS - EVIDENCE FOR A MACROPHAGE-DERIVED SOLUBLE FACTOR THAT DOWN-REGULATES DNA-SYNTHESIS IN SMOOTH-MUSCLE CELLS

Macrophages and smooth muscle cells (SMCs) are two of the major reacti ve cell types in atherosclerosis, a disease characterized by uncontrol led proliferation of SMCs. The present study was designed to determine how dietary oils containing gamma-linolenic acid (GLA) (primrose oil [PO]) and long-chain n-3 fatty acids (fish oil) influence the ability of macrophages to modulate SMC DNA synthesis in vitro. Mice were fed o ne of four diets containing 10% (wt/wt) corn oil (GO), PO, fish oil-CO mix (FC; 9:1, wt/wt), or fish oil-PO mix (FP; 1:3, wt/wt) for 2 weeks . Resident peritoneal macrophages were isolated from these mice and se eded on a semipermeable membrane with a 30-kDa cutoff. Macrophages wer e preincubated with or without 50 mu mol/L indomethacin (a cyclooxygen ase inhibitor) or 50 mu mol/L L655,238 (a 5-lipoxygenase inhibitor) fo r 30 minutes and subsequently cocultured with naive murine aortic SMCs grown on culture dishes. DNA synthesis in SMCs and prostaglandin form ation in coculture supernatants were measured at the end of a 39-hour incubation period. SMC DNA synthesis was inhibited by 28% and 60% in P O and FP diets containing 10.1% and 8.2% GLA, respectively, relative t o the control CO diet containing no GLA or long-chain n-3 fatty acid. A fourfold increase in the levels of PGE(1), a potent antiproliferativ e eicosanoid derived from GLA, was observed in the PO and FP groups re lative to the control CO group. Although PGE, levels were not differen t between the CO and FC dietary groups, 15% inhibition of SMC DNA synt hesis, relative to that in mice fed the control CO diet, was observed in mice fed the FC diet containing 13.3% 20:5n-3 and 7.6% 22:6n-3 fatt y acids. Macrophage inhibition of SMC DNA synthesis and proliferation in mice consuming GLA-enriched diets was blocked by indomethacin but n ot by L655,238. Addition of exogenous PGE, (100 nmol/L) reversed the e ffect of indomethacin. In experiments in which mice were fed increasin g levels of GLA-containing triglycerides, the ability of macrophages t o downregulate SMC proliferation was modulated in a dose-dependent fas hion. These data indicate that macrophages isolated from animals consu ming diets supplemented with dietary oils containing GLA reduce SMC DN A synthesis and proliferation in a cycle oxygenase-dependent manner an d therefore may favorably modulate the atherogenic process.