p38 Mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-κB 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-kappa B 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 mu M for 6-48 h. Palmitate at 100, 200, or 300 mu M markedly increased apoptosis after 12 h of incubation. This apoptotic effect was time (P = 0.008) and dose (P = 0.006) dependent. Palmitate (100 mu M for 24 h) induced a greater than 2-fold increase in apoptosis, which was accompanied with a 4-fold increase in p38MAPKactivity (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-kappa B (I kappa B). However, treatment of cells with SB203580 did not restore I kappa B 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 I kappa B degradation in hCAECs is independent of p38 MAPK activity.