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Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice

Oncogene volume 18, pages 3821–3830 (1999)Cite this article

Abstract

Leukocyte tyrosine kinase (LTK) is a receptor-type protein tyrosine kinase belonging to the insulin receptor superfamily. To elucidate its biological role, we generated transgenic mice expressing LTK under the control of cytomegarovirus enhancer and β-actin promoter. The transgenic mice exhibited growth retardation and most of the transgenic mice died within several months after birth. Interestingly, although LTK was expressed in several major organs, the activation (tyrosine-phosphorylation, kinase activity, and multimerization) of LTK was observed selectively in the heart, where LTK was localized on intracellular membrane, presumably on endoplasmic reticulum. Echocardiography showed that the transgenic heart underwent severe concentric hypertrophy, which resulted in reduced cardiac output, low blood pressure, and increased heart rate. Histological examination of the heart exhibited focal degeneration of cardiomyocytes. These histological changes were considered to be due to apoptosis, based on the finding that the sarcolemmas of the degenerative cardiomyocytes were well preserved. In addition, expression of fetal genes, such as atrial natriuretic peptide and skeletal α-actin, was markedly induced in the transgenic heart. These results indicate that a certain tissue-specific mechanism of activating LTK exists in the heart and that the activated LTK resulted in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming. These findings will provide novel insights into the activating mechanism and biological role of LTK in vivo.

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Acknowledgements

We thank Dr Jun-ichi Miyazaki for pUCCAGGS expression vector and thank Dr Yoshihide Tsujimoto for anti-bcl-2 antibody. We also thank Nobuyoshi Machiyama for photographs. This work was in parts supported by Grants-in-Aids from the Ministry of Education, Science and Culture of Japan and Mochida Memorial Foundation For Medical and Pharmaceutical Research.

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Author notes

  1. Koichiro Harada and Hisamaru Hirai: H Hirai and K Harada equally contributed to this work

Authors and Affiliations

  1. Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113, Japan

    Hiroaki Honda, Koichiro Harada, Issei Komuro, Hiroo Ueno, Yuji Tanaka, Yoshio Yazaki & Hisamaru Hirai

  2. Third Department of Internal Medicine, Faculty of Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki-shi, Osaka, 569, Japan

    Fumio Terasaki & Keishiro Kawamura

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  1. Hiroaki Honda
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Honda, H., Harada, K., Komuro, I. et al. Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice. Oncogene 18, 3821–3830 (1999). https://doi.org/10.1038/sj.onc.1202736

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