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Molecular Basis for Cardiac Adaptation to Overload

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Recent Progress in Failing Heart Syndrome

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Summary

The process of enlargement of the heart due to overload involves a significant reconstitution of the organ, including myocytes and intracellular constituents. We demonstrated the distribution of two types of cardiac myosin heavy chains (HCα and HCβ) in the human heart using monoclonal antibodies. The ventricle comprised mainly of HCβ has low ATPase activity, whereas the atrium was predominantly composed of HCα and has high ATPase activity. We also demonstrated isozymic transition of HCα to HCβ in the human atrium and ventricle by hemodynamic overload, regarded as a compensatory mechanism to meet an increased demand in work.

To examine the possibility that this isozymic transition of HCs due to overload is associated with the expression of the genes, we have isolated human HCα and HCβ cDNA clones from a fetal heart cDNA library. Comparison of the nucleotide and amino acid sequences deduced from these cDNA clones showed 91 and 96% homology, respectively. Using HCα and HCβ gene-specific sequences, we demonstrated that the transition of HCα to HCβ in the overloaded human heart was induced by the expression of HCβ gene.

To determine the role of cellular oncogenes in the process of cardiac growth and hypertrophy, we examined the expression pattern of eight cellular oncogenes during the developmental stage and pressure-overloaded hypertrophy of the rat heart by Northern blot analysis. c-fos, c-myc and c-Ha-ras were expressed in the heart in response to pressure overload and in a stage-specific manner, suggesting that these cellular oncogenes participate in the normal developmental process and hypertrophy of the heart. We also cloned the genes of which the expression level was rapidly changed by pressure overload by a differential hybridization technique. Our results suggest that clone 4 may be involved in the development of cardiac hypertrophy due to overload.

Finally, we examined the molecular mechanisms by which mechanical stimuli induce cardiac hypertrophy and specific gene expression. For this purpose, we cultured rat neonatal cardiocytes in deformable dishes and imposed mechanical load by stretching the adherent cells. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos and skeletal α-actin. The transfected chloramphenicol acetyltranferase gene linked to upstream sequences of the fos gene indicated that sequences containing a serum response element were required for efficient transcription by stretching.

The accumulation of c-fos mRNA by stretching was suppressed by protein kinase C inhibitors at the transcriptional level. Moreover, myocyte stretching increased inositol phosphate levels. We concluded from these data that mechanical stimuli might directly induce cardiac hypertrophy and specific gene expression, possibly via protein kinase C activation.

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Authors and Affiliations

  1. Third Department of Internal Medicine, The Faculty of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, 113, Japan

    Yoshio Yazaki, Masahiko Kurabayashi & Issei Komuro

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  1. Yoshio Yazaki
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  2. Masahiko Kurabayashi
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  3. Issei Komuro
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Editors and Affiliations

  1. The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, 930-01, Toyama, Japan

    Shigetake Sasayama M.D. (Professor of Medicine) (Professor of Medicine)

  2. Okayama University Medical School, 2-5-1, Shikata-cho, 700, Okayama, Japan

    Hiroyuki Suga M.D., D.M. SC. (Professor of Physiology) (Professor of Physiology)

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© 1991 Springer-Verlag Tokyo

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Yazaki, Y., Kurabayashi, M., Komuro, I. (1991). Molecular Basis for Cardiac Adaptation to Overload. In: Sasayama, S., Suga, H. (eds) Recent Progress in Failing Heart Syndrome. Springer, Tokyo. https://doi.org/10.1007/978-4-431-67955-4_2

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  • DOI: https://doi.org/10.1007/978-4-431-67955-4_2

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-68019-2

  • Online ISBN: 978-4-431-67955-4

  • eBook Packages: Springer Book Archive

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