© 1996 American Heart Association, Inc.
Articles |
Oleic Acid–Induced Mitogenic Signaling in Vascular Smooth Muscle Cells
A Role for Protein Kinase C
the Department of Cellular and Molecular Pharmacology, Medical University of South Carolina, Charleston.
Correspondence to Brent M. Egan, MD, Division of Clinical Pharmacology, Medical University of South Carolina, 171 Ashley Ave, CSB 826H, Charleston, SC 29425.
As an initial step in testing the hypothesis that high oleic acid concentrations contribute to vascular remodeling in obese hypertensive patients by activating protein kinase C (PKC), the effects of oleic acid on primary cultures of rat aortic smooth muscle cells (RASMCs) were studied. Oleic acid, an 18-carbon cis-monounsaturated fatty acid (18:1 [cis]), from 25 to 200 µmol/L significantly increased [3H]thymidine uptake in RASMCs with an EC50 of 41.0 µmol/L and a maximal response of 196±15% of control (P<.01). Oleic acid from 25 to 200 µmol/L caused a concentration-dependent increase in the number of RASMCs in culture at 6 days, reaching a maximum of 210±13% of control at 100 µmol/L (P<.001). PKC inhibition with 4 µmol/L bisindolylmaleimide I and PKC depletion (
, µ, 
, and 
) with 24-hour exposure to 200 nmol/L phorbol 12-myristate 13-acetate in RASMCs eliminated the mitogenic effects of oleic acid but did not reduce responses to 10% FBS. Stimulation of intact cells with oleic acid induced a peak increase of cytosolic PKC activity, reaching 328±8% of control (P<.001), but did not enhance PKC activity in the membrane fraction (105±4%, P=NS). The oleic acid–induced increase of PKC activity in cell lysates was similar in the presence and absence of Ca2+, phosphatidylserine, and diolein (maximum response, 360±4% versus 342±9% of control, P=NS). Unlike phorbol 12-myristate 13-acetate, oleic acid over 24 hours did not downregulate any of the four PKC isoforms detected in RASMCs. Oleic acid treatment activated mitogen-activated protein (MAP) kinase. PKC depletion in RASMCs eliminated the rise in thymidine uptake, activation of PKC, and activation of MAP kinase in response to oleic acid. In contrast to oleic acid, 50 to 200 µmol/L stearic (18:0) and elaidic (18:1 [trans]) acids, which are less effective activators of PKC than oleic acid, did not enhance thymidine uptake. These data suggest that oleic acid induces proliferation of RASMCs by activating PKC, particularly one or more of the Ca2+-independent isoforms, and raise the possibility that the higher oleic acid concentrations observed in obese hypertensive patients may contribute to vascular remodeling.
Key Words: oleic acid • protein kinase C • mitogenesis • vascular smooth muscle cell • vascular remodeling
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