EFFECTS OF OXIDISED LDL ON NITRIC OXIDE AND ENDOTHELIN-1 PRODUCTION IN HUMAN MICROVASCULAR ENDOTHELIUM: ROLE OF THROMBOXANE A2 RECEPTOR

Abstract

LDL particles modulate the release of NO and endothelin-1 by the endothelium. To what extent these effects depend on LDL concentration and degree of oxidation and eventually what is the role of tromboxane A2 receptor is unknown. HMEC-1 were exposed for 24-h to a) 3 concentrations (50, 100 and 200 ?g/ml) of either native, low- or medium-oxidised LDL, b) 8-epi-PGF2? (F2?IP, 10-11, 10-10, 10-9, and 10-8 M) either alone or with TXA2 receptor blocker SQ 29.548 (10-6 M), c) native, low- and medium-oxidised LDL either alone or with SQ 29.548 (10-6 M). In all experiments intracellular eNOS, and NO2/NO3, endothelin-1 and interleukin-6 concentration in the medium were measured. Both native and oxidised LDL induced a NO2/NO3 accumulation with dose and degree of oxidation acting synergistically; eNOS was stimulated only by oxidised LDL. F2?IP, NO2/NO3 and eNOS with SQ 29.548 completely preventing these effects but only partially the effect of LDL. IL-6 was also synergistically stimulated by LDL dose and degree of oxidation but not by direct exposure to F2?IP nor was affected by SQ 29.548. Both native and oxidised LDL stimulated endothelin-1 production independently of dose or degree of oxidation. F2?IP had a modest stimulatory effect while the effect of SQ 29.548 was evident only with oxidised LDL. In HMEC-1 LDL dose and degree of oxidation synergistically stimulate NO and IL-6 production and the effect on NO is largely mediated through the TXA2 receptor. LDL simultaneously facilitate endothelin-1 production independently of the dose and degree of oxidation