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Myosin light chain kinase mediates sarcomere organization during cardiac hypertrophy in vitro

Nature Medicine volume 6, pages 183–188 (2000)Cite this article

Abstract

During the development of hypertrophy, cardiac myocytes increase organization of the sarcomere, a highly ordered contractile unit in striated muscle cells. Several hypertrophic agonists, such as angiotensin II, phenylephrine, and endothelin-1, have been shown to promote the sarcomere organization. However, the signaling pathway, which links extracellular stimuli to sarcomere organization, has not been clearly demonstrated. Here, we demonstrate that myosin light chain kinase specifically mediates agonist-induced sarcomere organization during early hypertrophic response. Acute administration of a hypertrophic agonist, phenylephrine, or angiotensin II, causes phosphorylation of myosin light chain 2v both in cultured cardiac myocytes and in the adult heart in vivo. We also show that both sarcomere organization and myosin light chain 2v phosphorylation are dependent on the activation of Ca2+/calmodulin pathway, a known activator of myosin light chain kinase. These results define a new and specific role of myosin light chain kinase in cardiac myocytes, which may provide a rapid adaptive mechanism in response to hypertrophic stimuli.

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Figure 1: Effect of cycloheximide on Ang II-induced sarcomere organization.
Figure 2: Agonist-induced phosphorylation of MLC2v.
Figure 3: Effect of activated MLCK on sarcomere organization in cardiac myocytes.
Figure 4: Role of Ca2+/calmodulin-MLCK pathway and mechanical activity in Ang II-Induced sarcomere organization.
Figure 5: Effect of the activated MLCK on other phenotypes of cardiac hypertrophy.

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Acknowledgements

We thank J. T. Stull for the plasmid, A. Horowitz, A. Haunstetter, M. Ikebe and G. Zhi for discussions, P. Kang, K Sato, and E.O. Weinberg for experimental help and discussions, and J. Hampe for technical assistance. Supported by NIH grant to S.I. and AHA-Michigan grant to J.S. H.A. was supported by AHA-Michigan and AHA-Massachusetts fellowships.

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Authors and Affiliations

  1. Cardiovascular Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, 330 Brookline Ave, SL-201, Boston, 02215, Massachusetts, USA

    Hiroki Aoki & Seigo Izumo

  2. Weis Center for Research, Pennsylvania State University College of Medicine, Danville, 17822-2601, Pennsylvania, USA

    Junichi Sadoshima

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Correspondence to Seigo Izumo.

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Aoki, H., Sadoshima, J. & Izumo, S. Myosin light chain kinase mediates sarcomere organization during cardiac hypertrophy in vitro. Nat Med 6, 183–188 (2000). https://doi.org/10.1038/72287

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