Modulation of cyclin D1 and early growth response factor-1 gene expression in interleukin-1beta-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-1beta, 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-1beta 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.
Bousserouel
Souad
S
UMR 7079 Physiologie et Physiopathologie, Université Pierre et Marie Curie, Paris, France.
Raymondjean
Michel
M
Brouillet
Arthur
A
Béréziat
Gilbert
G
Andréani
Marise
M
D000818:Animals; D002417:Cattle; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005231:Fatty Acids, Unsaturated; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins