© 1997 American Heart Association, Inc.
Articles |
Regulation of Scavenger Receptor Expression in Smooth Muscle Cells by Protein Kinase C
A Role for Oxidative Stress
From the Gladstone Institute of Cardiovascular Disease (M.M., A.F., R.E.P.), the Cardiovascular Research Institute (M.M., R.E.P.), and the Departments of Pediatrics (M.M.) and Pathology (R.E.P.), University of California at San Francisco, and the Division of Cellular and Molecular Medicine and Endocrinology and Metabolism (C.K.G.), University of California at San Diego, La Jolla.
Correspondence to Robert E. Pitas, PhD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100.
Abstract Phorbol esters increase scavenger-receptor mRNA expression and receptor activity in smooth muscle cells (SMCs). Our present results demonstrate that activation of protein kinase C (PKC) mediates this increase in receptor expression. This conclusion is based on the findings that (1) phorbol esters induced translocation of PKC-
from the cytosol to the membrane fraction; (2) PKC inhibitors blocked the effect of phorbol esters on receptor expression; (3) diacylglycerol, a physiological PKC agonist, enhanced scavenger-receptor activity; and (4) in cotransfected human SMCs, constitutively active PKC- stimulated the expression of a reporter gene under control of the scavenger-receptor promoter. Phorbol ester treatment of SMCs increased intracellular reactive oxygen, and the increase in receptor activity was reduced 30% by the antioxidant N-acetyl cysteine (NAC), suggesting a role for reactive oxygen in phorbol ester–mediated receptor regulation. Furthermore, direct treatment of SMCs with reactive oxygen species increased scavenger-receptor activity. In rabbit SMCs, 100 µmol/L H2O2 alone slightly increased scavenger-receptor mRNA and protein expression. In combination, 100 µmol/L H2O2 and 10 µmol/L vanadate, which promotes formation of OH and enhances the inhibition of protein tyrosine phosphatase by H2O2, increased scavenger-receptor mRNA expression 25-fold in rabbit SMCs and 8-fold in human SMCs. NAC reduced the effect of H2O2 and vanadate by 93%. The increase in SMC scavenger-receptor expression occurs at the level of gene transcription. Receptor mRNA half-life was unchanged after treatment with either phorbol esters or reactive oxygen (
14.5 hours), and induction by phorbol esters increased SMC scavenger-receptor mRNA transcription, as determined by nuclear run-on assay. Multiple cytokines and growth factors that contribute to the generation of reactive oxygen species are present in atherosclerotic lesions. These factors may all contribute to the upregulation of SMC scavenger-receptor activity and therefore to the formation of smooth muscle foam cells.
Key Words: scavenger receptor • receptor regulation • reactive oxygen • protein kinase C
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