DIETARY GAMMA-LINOLENIC ACID ENHANCES MOUSE MACROPHAGE-DERIVED PROSTAGLANDIN E-1 WHICH INHIBITS VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

We previously demonstrated that macrophages isolated from mice fed gam ma-linolenic acid (GLA)-enriched diets reduce vascular smooth muscle c ell (SMC) proliferation in a cyclooxygenase-dependent fashion and may therefore favorably modulate the atherogenic process. The present stud y was conducted to elucidate the mechanism(s) by which dietary GLA inf luences the ability of macrophages to modulate SMC growth programs. Re sident peritoneal macrophages were isolated from C57BL/6 female mice f ed diets containing variable GLA compositions at 10% (wt/wt), treated with various antibodies and co-cultured with cycling naive vascular SM C isolated from nonpurified diet-fed mice. Smooth muscle cell prolifer ation and intracellular cAMP levels were measured after cc-culture. In parallel experiments, cycling naive vascular SMC isolated from nonpur ified diet-fed mice were dosed with exogenous prostaglandin E-1 (PGE(1 )) for various periods and challenged with cycloheximide for 4 h (8-12 h after PGE(1) addition), and intracellular cAMP levels were measured at various time points. Macrophages isolated from mice fed GLA-enrich ed dietary oils significantly reduced SMC proliferation in co-culture compared with controls (macrophages from mice fed a corn oil diet cont aining no GLA). Anti-PGE(1) antiserum treatment (1:50 or 1:100) blocke d the ability of GLA-enriched macrophages to down-regulate SMC prolife ration, a response reversed by exogenous PGE(1) treatment. Macrophages isolated from mice fed GLA-enriched dietary oils elevated SMC intrace llular cAMP levels in a biphasic fashion. In addition, exogenous PGE(1 ) (1 nmol/L to 10 mu mol/L) exerted a similar biphasic cAMP response i n SMC, and the second phase of cAMP elevation was antagonized by cyclo heximide. in conclusion, dietary GLA enhances mouse macrophage-derived prostaglandin E-1, which inhibits vascular SMC proliferation.