N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-gamma pathways.
Fish oil supplementation is associated with lower risk of coronary artery disease in humans, and it has been shown to reduce ectopic calcification in an animal model. However, whether N-3 fatty acids, active ingredients of fish oil, have direct effects on calcification of vascular cells is not clear. In this report, we investigated the effects of eicosapentaenoic acid and docosahexaenoic acid (DHA) on osteoblastic differentiation and mineralization of calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells that undergo osteoblastic differentiation and form calcified matrix in vitro. Results showed that N-3 fatty acids inhibited alkaline phosphatase (ALP) activity and mineralization of vascular cells, suggesting that they directly affect osteoblastic differentiation in vascular cells. By Western blot analysis, DHA activated p38-mitogen-activated protein kinase (MAPK) but not extracellular-regulated kinase (ERK) or Akt. An inhibitor of p38-MAPK partially reversed the inhibitory effects of DHA on osteoblastic differentiation and mineralization. Transient transfection experiments showed that DHA also activated peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Both p38-MAPK activator and PPAR-gamma agonists reproduced the inhibitory effects of DHA on CVC mineralization. Pretreatment with DHA also inhibited interleukin-6-induced ALP activity and mineralization. Together, these results suggest that N-3 fatty acids directly inhibit vascular calcification, and that the inhibitory effects are mediated by the p38-MAPK and PPAR-gamma pathways.
Abedin
M
M
Department of Medicine, University of California, Los Angeles, CA, USA.
Lim
J
J
Tang
T B
TB
Park
D
D
Demer
L L
LL
Tintut
Y
Y
D000818:Animals; D002114:Calcinosis / Q000517:prevention & control*; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014652:Vascular Diseases / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D015525:Fatty Acids, Omega-3; D015850:Interleukin-6; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D048051:p38 Mitogen-Activated Protein Kinases