Abstract
We recently reported that interleukin-1beta (IL-1beta) induces a novel form of cardiac myocyte hypertrophy characterized by an increase in protein content but an absence of the fetal program of skeletal alpha-actin or beta-myosin heavy chain (beta-MHC) gene expression (Palmer, J. N., Hartogensis, W. E., Patten, M., Fortuin, F. D., and Long, C. S. (1995) J. Clin. Invest. 95, 2555-2564). Because of the apparent disparity between this myocardial phenotype and that seen with other hypertrophic agents in culture, such as catecholamines, we investigated the effect of IL-1beta on alpha1-induced cardiomyocyte hypertrophy. Although there was no augmentation in total protein when IL-1beta and phenylephrine were given simultaneously, IL-1beta attenuated the increase in contractile protein mRNAs (skeletal alpha-actin and beta-MHC) in response to phenylephrine. Transient transfection studies with skeletal alpha-actin and beta-MHC promoter constructs linked to the chloramphenicol acetyltransferase (CAT)-reporter gene indicate that repression occurred at the level of gene transcription. In view of the previously reported activity of the zinc finger protein YY1 in the negative regulation of the skeletal alpha-actin promoter in cardiomyocytes (MacLellan, W. R., Lee, T. C., Schwartz, R. J., and Schneider, M. D. (1994) J. Biol. Chem. 269, 16754-16760), we investigated the potential role of this factor in the IL-1beta-mediated effects. Using transient transfection, we found that a mutation in the YY1 binding site of the skeletal alpha-actin promoter abolished the inhibitory effect of IL-1beta. We further found that the 127-base pair fragment of the skeletal alpha-actin promoter required for the IL-1beta effect is also required for inhibition by the overexpression of YY1 in the myocytes. Furthermore, increased levels of YY1 protein are found in IL-1beta treated myocytes. Taken together these results suggest that the repression of contractile protein gene transcription by IL-1beta may be due, at least in part, to activation of the negative transcription factor YY1.
Highlights
From the Division of Cardiology Section and the Research Service, Veterans Affairs Medical Center, San Francisco, California 94121 and the Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, California 94143
We recently reported that interleukin-1 (IL-1) induces a novel form of cardiac myocyte hypertrophy characterized by an increase in protein content but an absence of the fetal program of skeletal ␣-actin or -myosin heavy chain (-MHC) gene expression
Because of the apparent disparity between this myocardial phenotype and that seen with other hypertrophic agents in culture, such as catecholamines, we investigated the effect of IL-1 on ␣1-induced cardiomyocyte hypertrophy
Summary
Vol 271, No 35, Issue of August 30, pp. 21134 –21141, 1996 Printed in U.S.A. From the Division of Cardiology Section and the Research Service, Veterans Affairs Medical Center, San Francisco, California 94121 and the Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, California 94143. In view of the antagonistic effects of cytokines on adrenergic signaling in vivo and our observations on the failure of IL-1 to induce the fetal program of gene transcription, we hypothesized that IL-1 could act as a negative modulator of the myocyte proteins regulated by catecholamines. Our results show that IL-1 acts as a negative regulator of ␣1-adrenergic induced skeletal ␣-actin and -MHC gene expression This repression is a direct result of action at the transcriptional level and may involve the bifunctional transcription factor YY1. To our knowledge this is the first report on the active repression of an induced cardiomyocyte phenotype in culture These findings may provide a mechanism for the reported negative inotropic effect of cytokines such as IL-1 on myocardial function in vivo and may provide new insight into the mechanism(s) responsible for the expression of the differentiated phenotype by cardiac myocytes
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