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 majo r phospholipid component of oxidized LDL, stimulate the production of endot helin-1 (ET)-1 in cultured human coronary artery smooth muscle cells (SMCs) , and (2) to examine the possible effect of an antiatherogenic agent, eicos apentaenoic acid (EPA), on oxidized-LDL- and lyse-PC-stimulated ET-1 produc tion 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) sig nificantly 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 p roduction stimulated by oxidized LDL and lyse-PC in a concentration-depende nt 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 acti vation. Results suggest that oxidized LDL and lyse-PC stimulate ET-1 produc tion 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 rou gh the modulation of PKC in human coronary artery SMCs. EPA may exert an an tiatherosclerotic effect, in part, through these mechanisms. Copyright (C) 2001 S. Karger AG, Basel.