Inhibition by eicosapentaenoic acid of oxidized-LDL- and lysophosphatidylcholine-induced human coronary artery smooth muscle cell production of endothelin

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 lyse-PC-stimulated ET-1 production in these cells. Oxidized LDL (10-50 mug/ml) and lyse-PC (10(-7) to 10(-5) mol/l) stimulated ET-1 production in a concentration-dependent manner. By contrast, the effects of native LDL and phosphatidylcholine were modest or absent. Lyse-PC (10-7 to 10-5 mol/l) and oxidized LDL (10-50 mug/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 mu mol/l) clearly suppressed ET-1 production stimulated by oxidized LDL and lyse-PC in a concentration-dependent man ner. Furthermore, EPA (160 mu mol/l) significantly inhibited lyse-PC (10(-5) mol/l)- and oxidized LDL (50 mug/ mil-induced particulate PKC activation. Results suggest that oxidized LDL and lyse-PC stimulate ET-1 production by a mechanism involving activation of PKC, and that EPA suppresses ET-1 production stimulated by lyse-PC as well as oxidized LDL probably th rough the modulation of PKC in human coronary artery SMCs. EPA may exert an antiatherosclerotic effect, in part, through these mechanisms. Copyright (C) 2001 S. Karger AG, Basel.