Involvement of protein kinase C in the supersensitivity to 5-HT caused by oxidized low-density lipoproteins.

The effect of native (n-LDL) and oxidized (ox-LDL) low-density lipoproteins and lysophosphatidylcholines (LPCs) on: (1) vasodilator responses induced by acetylcholine (ACh) in intact rabbit aorta segments, and (2) vasoconstrictor responses to serotonin (5-HT), and potassium (K+) in endothelium denuded segments was investigated. In intact vessels, 100 microg/ml ox-LDL did not modify ACh-induced relaxation, while it was diminished by 300 microg/ml ox-LDL and abolished by 50 microM LPCs. In contrast, this relaxation was unaltered by n-LDL (100 or 300 microg/ml). In deendothelialized arteries, 100 and 300 microg/ml n-LDL as well as 50 microM LPCs did not modify the contractions induced by 5-HT or K+, while 100 or 300 microg/ml ox-LDL increased the 5-HT-induced contraction, without altering those induced by 75 mM K+. Incubation with 100 or 300 microg/ml ox-LDL increased the contractile response to the protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDB) (0.1-1 microM) in a concentration-dependent manner, which was blocked by staurosporine (0.1 microM), and unaltered by (50 microM) calphostin C or (50 microM) chelerythrine, the three are PKC inhibitors. Preincubation with 0.05 microM PDB increased the contraction elicited by 5-HT, while staurosporine decreased the PDB-induced contraction, and prevented the 5-HT response increase caused by 300 microg/ml ox-LDL. These results suggest that only ox-LDL reduces endothelium-dependent relaxation and elicits PKC activation, and that this activation mediates, at least in part, the vasoconstrictor response to 5-HT.