p38 mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-kappaB degradation in human coronary artery endothelial cells.
Plasma free fatty acids are elevated in patients with type 2 diabetes and contribute to the pathogenesis of insulin resistance and endothelial dysfunction. The p38 MAPK mediates stress, inflammation, and apoptosis. Whether free fatty acids induce apoptosis and/or activate nuclear factor-kappaB inflammatory pathway in human coronary artery endothelial cells (hCAECs) and, if so, whether this involves the p38 MAPK pathway is unknown. hCAECs (passages 4-6) were grown to 70% confluence and then incubated with palmitate at concentrations of 0-300 microm for 6-48 h. Palmitate at 100, 200, or 300 microm markedly increased apoptosis after 12 h of incubation. This apoptotic effect was time (P=0.008) and dose (P=0.006) dependent. Palmitate (100 microm for 24 h) induced a greater than 2-fold increase in apoptosis, which was accompanied with a 4-fold increase in p38 MAPK activity (P<0.001). Palmitate did not affect the phosphorylation of Akt1 or ERK1/2. SB203580 (a specific inhibitor of p38 MAPK) alone did not affect cellular apoptosis; however, it abolished palmitate-induced apoptosis and p38 MAPK activation. Palmitate significantly reduced the level of inhibitor of nuclear factor-kappaB (IkappaB). However, treatment of cells with SB203580 did not restore IkappaB to baseline. We conclude that palmitate induces hCAEC apoptosis via a p38 MAPK-dependent mechanism and may participate in coronary endothelial injury in diabetes. However, palmitate-mediated IkappaB degradation in hCAECs is independent of p38 MAPK activity.
Chai
Weidong
W
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, P.O. Box 801410, Charlottesville, Virginia 22908-1410, USA.
Liu
Zhenqi
Z
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D020672:I-kappa B Proteins; D019308:Palmitic Acid; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases