Modulation of cyclin D1 and early growth response factor‐1 gene expression in interleukin‐1β‐treated rat smooth muscle cells by n‐6 and n‐3 polyunsaturated fatty acids

The proliferation of smooth muscle cells (SMC) is a key event in the development of atherosclerosis. In addition to growth factors or cytokines, we have shown previously that n‐3 polyunsaturated fatty acids (PUFAs) act in opposition to n‐6 PUFAs by modulating various steps of the inflammatory process. We have investigated the molecular mechanisms by which the incorporation of the n‐6 PUFA, arachidonic acid, increases the proliferation of rat SMC treated with interleukin‐1β, while the n‐3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit no mitogenic response. Incorporation of EPA or DHA into SMC, which are then activated by interleukin‐1β to mimic inflammation, decreases promoter activity of the cyclin D1 gene and phosphorylation of the retinoblastoma protein. Together, our data demonstrate that n‐3 effects are dependent on the Ras/Raf‐1/extracellular signal regulated kinase (ERK)/mitogen‐activated protein kinase pathway, and that down‐regulation of the cyclin D1 promoter activity is mediated by the specific binding of the early growth response factor‐1. Finally, we have shown that the incorporation of EPA and DHA also increased the concentration of caveolin‐1 and caveolin‐3 in caveolae, which correlated with n‐3 PUFA inhibition of SMC proliferation through the mitogen‐activated protein kinase pathway. We provide evidence indicating that, in contrast to n‐6 PUFAs, n‐3 PUFAs exert antiproliferative effects on SMC through the mitogen‐activated protein kinase/ERK pathway.