11 July 2001
The objectives of the present study were (1) to determine whether oxidized low-density lipoprotein (LDL) and lysophosphatidylcholine (lyso-PC), a major phospholipid component of oxidized LDL, stimulate the production of endothelin-1 (ET)-1 in cultured human coronary artery smooth muscle cells (SMCs), and (2) to examine the possible effect of an antiatherogenic agent, eicosapentaenoic acid (EPA), on oxidized-LDL- and lyso-PC-stimulated ET-1 production in these cells. Oxidized LDL (10–50 µg/ml) and lyso-PC (10<sup>–7</sup> to 10<sup>–5</sup> mol/l) stimulated ET-1 production in a concentration-dependent manner. By contrast, the effects of native LDL and phosphatidylcholine were modest or absent. Lyso-PC (10<sup>–7</sup> to 10<sup>–5</sup> mol/l) and oxidized LDL (10–50 µg/ml) significantly induced particulate protein kinase C (PKC) activation. Lyso-PC- and oxidized-LDL-stimulated ET-1 production was significantly inhibited by PKC inhibitor, PKC (19–36). EPA (80–160 µmol/l) clearly suppressed ET-1 production stimulated by oxidized LDL and lyso-PC in a concentration-dependent manner. Furthermore, EPA (160 µmol/l) significantly inhibited lyso-PC (10<sup>–5</sup> mol/l)- and oxidized LDL (50 µg/ml)-induced particulate PKC activation. Results suggest that oxidized LDL and lyso-PC stimulate ET-1 production by a mechanism involving activation of PKC, and that EPA suppresses ET-1 production stimulated by lyso-PC as well as oxidized LDL probably through the modulation of PKC in human coronary artery SMCs. EPA may exert an antiatherosclerotic effect, in part, through these mechanisms.