Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL-induced EGF-receptor activation

1 Oxidized low density lipoproteins (oxLDL) are thought to play a major rol e in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported th at the EGF receptor (EGFR) signalling pathway is activated by lipid peroxid ation products (among them 4-hydroxynonenal, 4-HNE) contained in oxLDL. 2 The use of phenolic antioxidants, such as trolox, alpha-tocopherol, caffe ic acid and tyrphostins A-25, A-46 or A-1478, showed that the oxLDL-induced EGFR activation is constituted by two separate components, the first (earl y) one being antioxidant-insensitive, the second (late) being antioxidant-s ensitive. 3 4-HNE derivatization of EGFR and EGFR activation induced by exogenous 4-H NE, suggest that the early (0.5-3 h) component of oxLDL-induced EGFR activa tion is mediated (at least in part) by 4-HNE (and possibly by other oxidize d lipids). This early component is antioxidant-insensitive. 4 The second component (4-5 h) of the oxLDL-induced EGFR activation is anti oxidant-sensitive, since it is blocked by antioxidants such as trolox, caff eic acid or PDTC, which act by blocking the cellular oxidative stress (H2O2 generation) evoked by oxLDL. Conversely, exogenous H2O2 induced EGFR autop hosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This effect is mediated in part through inhibition by oxi dative stress of protein tyrosine phosphatases involved in EGFR dephosphory lation.