© 1995 American Heart Association, Inc.
Articles |
Stimulation of Gs and Inhibition of Gi Protein Functions by Minimally Oxidized LDL
From the Departments of Medicine (F.P., A.M.F., J.A.B.) and Pathology (Z.T.F., B.Y., J.A.B.), UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Farhad Parhami, Division of Cardiology, UCLA Center for Health Sciences, Rm 47-123, 10833 Le Conte Ave, Los Angeles, CA 90095.
Abstract We have previously shown that treatment of aortic endothelial cells with minimally oxidized LDL (MM-LDL) induces their interaction with monocytes but not neutrophils and that these induced responses are associated with increased cAMP levels. Here we studied the mechanism by which MM-LDL elevates cAMP levels. Treatment of human aortic endothelial cells with MM-LDL resulted in a saturable dose-dependent increase in cAMP levels. Studies using a combination of pertussis toxin and MM-LDL suggested that part of the cAMP increase was due to the stimulation of Gs complexes. Studies with pertussis toxin–treated membranes in which Gi was completely inhibited were used to directly address the effect of MM-LDL on the Gs pathway. MM-LDL and an oxidized lipid (palmitoyl arachidonyl phosphatidylcholine), the effects of which mimic those of MM-LDL, caused a 40% to 100% increase in cAMP levels in these isolated membranes that was augmented by GTP, thus showing Gs stimulation. These results also show that MM-LDL increases cAMP levels by inhibiting Gi. MM-LDL inhibited ADP ribosylation of Gi by about 30% and completely abolished the ability of serotonin to interact with Gi complexes, whereas direct activation of Gi by mastoparan was not inhibited. This observation suggests that MM-LDL interferes with the interaction of Gi molecules with inhibitory receptors. There was no direct effect of MM-LDL on adenylate cyclase. Overall, these studies show that MM-LDL increases cAMP levels both by stimulating Gs and inhibiting Gi complexes.
Key Words: minimally oxidized LDL • G proteins • cAMP • ADP ribosylation
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