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. 1994 Apr 12;91(8):3468–3472. doi: 10.1073/pnas.91.8.3468

Posttranscriptional modification of myosin heavy-chain gene expression in the hypertrophied rat myocardium.

K Ojamaa 1, J F Petrie 1, C Balkman 1, C Hong 1, I Klein 1
PMCID: PMC43598  PMID: 8159771

Abstract

Hypertrophy of the myocardium in response to pressure or volume overload elicits a change in myofibrillar protein content as a result of changes in both transcriptional and translational regulation of gene expression. Hemodynamic overload caused by aortic constriction produced changes in the expression of the two isoforms of myosin heavy chain (MHC) with a 319% increase in beta-MHC mRNA and a 54% decrease in alpha-MHC mRNA (P < 0.01). Cardiac unloading as a result of heterotopic transplantation resulted in a decrease in cardiac mass and a similar shift in MHC isoform expression. In this study. We investigated cardiac gene transcription to understand how different hemodynamic stimuli produce similar cardiac phenotypes. We studied the in vivo activity of the alpha-MHC promoter (-2564 to +421 bp of the transcriptional start site) by directly injecting a recombinant expression plasmid (pAM3LUC) into the ventricular tissue of coarctated animals as well as into the unloaded heterotopic transplanted heart. When expressed as a function of the activity of a constitutively active viral promoter (pSVCAT), pAM3LUC activities were 18.4 +/- 2.9, 24.6 +/- 2.6, and 25.0 +/- 4.5 (x10(4)) luciferase/chloramphenicol acetyltransferase units in the hypertrophied ventricles of 2-, 3-, and 7-day coarctated animals, respectively. These values were not statistically different from pAM3LUC activity in control hearts of sham operated animals even though alpha-MHC mRNA content was decreased by 54% in the hypertrophied myocardium. This disparity between transcriptional activity and mRNA content suggests that alpha-MHC expression in the hypertrophic ventricle is in part regulated by a posttranscriptional mechanism. In contrast, alpha-MHC promoter activity in the unloaded transplanted hearts decreased significantly by 37% compared to control working hearts and suggests that a transcriptional mechanism of regulation of the alpha-MHC gene may account for the phenotypic expression observed in the unloaded myocardium.

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Selected References

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  1. Chassagne C., Wisnewsky C., Schwartz K. Antithetical accumulation of myosin heavy chain but not alpha-actin mRNA isoforms during early stages of pressure-overload-induced rat cardiac hypertrophy. Circ Res. 1993 Apr;72(4):857–864. doi: 10.1161/01.res.72.4.857. [DOI] [PubMed] [Google Scholar]
  2. Cooper G., 4th Cardiocyte adaptation to chronically altered load. Annu Rev Physiol. 1987;49:501–518. doi: 10.1146/annurev.ph.49.030187.002441. [DOI] [PubMed] [Google Scholar]
  3. Eleftheriades E. G., Durand J. B., Ferguson A. G., Engelmann G. L., Jones S. B., Samarel A. M. Regulation of procollagen metabolism in the pressure-overloaded rat heart. J Clin Invest. 1993 Mar;91(3):1113–1122. doi: 10.1172/JCI116270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Feldman A. M., Ray P. E., Silan C. M., Mercer J. A., Minobe W., Bristow M. R. Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation. 1991 Jun;83(6):1866–1872. doi: 10.1161/01.cir.83.6.1866. [DOI] [PubMed] [Google Scholar]
  5. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Imamura S., Matsuoka R., Hiratsuka E., Kimura M., Nakanishi T., Nishikawa T., Furutani Y., Takao A. Adaptational changes of MHC gene expression and isozyme transition in cardiac overloading. Am J Physiol. 1991 Jan;260(1 Pt 2):H73–H79. doi: 10.1152/ajpheart.1991.260.1.H73. [DOI] [PubMed] [Google Scholar]
  7. Izumo S., Lompré A. M., Matsuoka R., Koren G., Schwartz K., Nadal-Ginard B., Mahdavi V. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest. 1987 Mar;79(3):970–977. doi: 10.1172/JCI112908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Klein I., Hong C. Effects of thyroid hormone on cardiac size and myosin content of the heterotopically transplanted rat heart. J Clin Invest. 1986 May;77(5):1694–1698. doi: 10.1172/JCI112488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Klein I., Ojamaa K., Samarel A. M., Welikson R., Hong C. Hemodynamic regulation of myosin heavy chain gene expression. Studies in the transplanted rat heart. J Clin Invest. 1992 Jan;89(1):68–73. doi: 10.1172/JCI115587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Klein I., Samarel A. M., Welikson R., Hong C. Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis. Circ Res. 1991 Apr;68(4):1100–1107. doi: 10.1161/01.res.68.4.1100. [DOI] [PubMed] [Google Scholar]
  11. Ladenson P. W., Sherman S. I., Baughman K. L., Ray P. E., Feldman A. M. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5251–5255. doi: 10.1073/pnas.89.12.5251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Levy D., Garrison R. J., Savage D. D., Kannel W. B., Castelli W. P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990 May 31;322(22):1561–1566. doi: 10.1056/NEJM199005313222203. [DOI] [PubMed] [Google Scholar]
  13. McDermott P., Daood M., Klein I. Contraction regulates myosin synthesis and myosin content of cultured heart cells. Am J Physiol. 1985 Oct;249(4 Pt 2):H763–H769. doi: 10.1152/ajpheart.1985.249.4.H763. [DOI] [PubMed] [Google Scholar]
  14. Medford R. M., Nguyen H. T., Nadal-Ginard B. Transcriptional and cell cycle-mediated regulation of myosin heavy chain gene expression during muscle cell differentiation. J Biol Chem. 1983 Sep 25;258(18):11063–11073. [PubMed] [Google Scholar]
  15. Medford R. M., Wydro R. M., Nguyen H. T., Nadal-Ginard B. Cytoplasmic processing of myosin heavy chain messenger RNA: evidence provided by using a recombinant DNA plasmid. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5749–5753. doi: 10.1073/pnas.77.10.5749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mercadier J. J., Lompré A. M., Duc P., Boheler K. R., Fraysse J. B., Wisnewsky C., Allen P. D., Komajda M., Schwartz K. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest. 1990 Jan;85(1):305–309. doi: 10.1172/JCI114429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Morgan H. E., Baker K. M. Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation. 1991 Jan;83(1):13–25. doi: 10.1161/01.cir.83.1.13. [DOI] [PubMed] [Google Scholar]
  18. Nadal-Ginard B., Mahdavi V. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest. 1989 Dec;84(6):1693–1700. doi: 10.1172/JCI114351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ojamaa K., Klein I. In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone. Endocrinology. 1993 Mar;132(3):1002–1006. doi: 10.1210/endo.132.3.8440168. [DOI] [PubMed] [Google Scholar]
  20. Ojamaa K., Klein I. Thyroid hormone regulation of alpha-myosin heavy chain promoter activity assessed by in vivo DNA transfer in rat heart. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1269–1275. doi: 10.1016/0006-291x(91)91710-t. [DOI] [PubMed] [Google Scholar]
  21. Ojamaa K., Samarel A. M., Kupfer J. M., Hong C., Klein I. Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis. Am J Physiol. 1992 Sep;263(3 Pt 1):E534–E540. doi: 10.1152/ajpendo.1992.263.3.E534. [DOI] [PubMed] [Google Scholar]
  22. Parker T. G., Packer S. E., Schneider M. D. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990 Feb;85(2):507–514. doi: 10.1172/JCI114466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sadoshima J., Jahn L., Takahashi T., Kulik T. J., Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992 May 25;267(15):10551–10560. [PubMed] [Google Scholar]

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