Plasma free fatty acids (FFAs) are elevated in patients with type 2 diabetes and contribute to the pathogenesis of insulin resistance and endothelial dysfunction. The p38 mitogen-activated protein kinase (p38 MAPK) mediates stress, inflammation and apoptosis. Whether FFAs induce apoptosis and/or activate NF-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 to 6) were grown to 70% confluence and then incubated with palmitate at concentrations of 0 - 300 µM for 6 - 48 hrs. Palmitate at 100, 200 or 300 µM markedly increased apoptosis after 12 hrs of incubation. This apoptotic effect was time (p = 0.008) and dose (p = 0.006) dependent. Palmitate (100 µM for 24 hrs) induced a > 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 IB. However, treatment of cells with SB203580 did not restore IB 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 IB degradation in hCAECs is independent of p38 MAPK activity.