© 1997 American Heart Association, Inc.
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High Density Lipoproteins Stimulate Mitogen-Activated Protein Kinases in Human Skin Fibroblasts
From the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Wash (J.F.O., E.L.B.) and the Division of Endocrinology and Metabolism, Department of Medicine, Indiana University and the Richard L. Roudebush Veteran Affairs Medical Center, Indianapolis, Ind (M.A.D., R.F.B.).
Correspondence to John F. Oram, PhD, Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Box 356426, Seattle, WA 98195-6426. E-mail joram{at}u.washington.edu
Abstract Protein kinase C (PKC) seems to play an important role in many of HDL effects on cells, including removal of excess cholesterol. HDL removes cholesterol by at least two mechanisms. One mechanism involves desorption/diffusion of cholesterol from the plasma membrane onto the acceptor particle, whereas the second is mediated by apolipoproteins and may involve intracellular translocation of cholesterol to the plasma membrane for subsequent efflux. In this report, we examined the possibility that mitogen-activated protein (MAP) kinase is one of the downstream events from HDL activation of PKC. Using a gel kinase assay with myelin basic protein incorporated into the gel, HDL (50 µg protein/mL) stimulated multiple kinases of 42, 50, 52, 58, and 60 kDa. The 42-kDa protein kinase, corresponding to the unresolved MAP kinases ERK1 and ERK2 based on immunoblotting, was activated over 2-fold by HDL. HDL activated all identified kinases in a concentration- and time-dependent manner, which became maximal within 5 to 10 minutes and remained activated for at least 60 minutes. HDL activation of MAP kinase seems to be partially mediated by PKC, because down-regulation of PKC and known PKC inhibitors inhibited the HDL effect by 40 to 50%. Free apolipoproteins A-I (10 µg/mL) and A-II (10 µg/mL) had no significant effect on MAP kinase activation. Moreover, modifying HDL with trypsin or tetranitromethane, which abolishes apolipoprotein-mediated cholesterol efflux, had no effect on HDL activation of MAP kinase. These results suggest that HDL activates MAP kinase via multiple signal transduction pathways that are likely involved in an HDL effect unrelated to apolipoprotein-mediated cholesterol translocation and efflux.
Key Words: high density lipoprotein • MAP kinase • cholesterol transport • apolipoprotein A-I
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