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CIB1 is a regulator of pathological cardiac hypertrophy

Nature Medicine volume 16, pages 872–879 (2010)Cite this article

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Abstract

Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain–containing protein Ca2+ and integrin–binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain–containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca2+ channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin–nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, β isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.

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Figure 1: CIB1 is expressed in mouse and human heart.
Figure 2: CIB1 is necessary for pathological but not physiological hypertrophy and contributes to cardiac dysfunction during pressure overload.
Figure 3: CIB1 interacts with CnB.
Figure 4: CIB1 expression is necessary for sarcolemmal localization of CnB.
Figure 5: CIB1 facilitates calcineurin-NFAT activation.
Figure 6: Myocardial CIB1 overexpression enhances hypertrophy and calcineurin-NFAT signaling during pressure overload.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (J.D.M. and L.V.P.) and the Howard Hughes Medical Institute (J.D.M.) and by the Fondation Leducq (J.D.M. and H.D.). J.H. was supported in part by a grant from the Deutsche Forschungsgemeinschaft, Bonn, Germany (HE 3658/1-1) and the Cluster of Excellence Rebirth (also Deutsche Forschungsgemeinschaft). M.J.B. was supported by National Institutes of Health training grant 5 T32 HL07382 (principal investigator A. Schwartz).

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Author notes

  1. Helmut Drexler: Deceased.

  2. Joerg Heineke and Mannix Auger-Messier: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Howard Hughes Medical Institute, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Joerg Heineke, Mannix Auger-Messier, Robert N Correll, Jian Xu, Matthew J Benard & Jeffery D Molkentin

  2. Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Cluster of Excellence Rebirth, Hannover, Germany

    Joerg Heineke & Helmut Drexler

  3. Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Weiping Yuan & Leslie V Parise

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Contributions

J.H. and M.A.-M. performed and planned most of the experimentation with technical help from J.X., R.N.C. and M.J.B. W.Y. and L.V.P. provided Cib1−/− mice and recombinant CIB1 protein. J.D.M. and J.H. planned and supervised all experimentation. H.D. provided experimental support and ideas for the project. J.H. and J.D.M. wrote the paper.

Corresponding authors

Correspondence to Joerg Heineke or Jeffery D Molkentin.

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Heineke, J., Auger-Messier, M., Correll, R. et al. CIB1 is a regulator of pathological cardiac hypertrophy. Nat Med 16, 872–879 (2010). https://doi.org/10.1038/nm.2181

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