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.
Encabo
A
A
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Ferrer
M
M
Conde
M V
MV
Porres
A
A
Gómez-Gerique
J A
JA
Marín
J
J
Balfagón
G
G
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D019311:Staurosporine; D000109:Acetylcholine; D011188:Potassium