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CIB1 is a regulator of pathological cardiac hypertrophy

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.

References

  1. Rosamond, W. et al. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117, e25–e146 (2008).

    PubMed  Google Scholar 

  2. Levy, D., Larson, M.G., Vasan, R.S., Kannel, W.B. & Ho, K.K. The progression from hypertension to congestive heart failure. J. Am. Med. Assoc. 275, 1557–1562 (1996).

    Article  CAS  Google Scholar 

  3. Heineke, J. & Molkentin, J.D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589–600 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Bueno, O.F., van Rooij, E., Molkentin, J.D., Doevendans, P.A. & De Windt, L.J. Calcineurin and hypertrophic heart disease: novel insights and remaining questions. Cardiovasc. Res. 53, 806–821 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Buch, M.H. et al. The sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit. J. Biol. Chem. 280, 29479–29487 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Frey, N., Richardson, J.A. & Olson, E.N. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc. Natl. Acad. Sci. USA 97, 14632–14637 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Heineke, J. et al. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc. Natl. Acad. Sci. USA 102, 1655–1660 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jeong, D. et al. PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circ. Res. 102, 711–719 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Politino, M. & King, M.M. Calcineurin-phospholipid interactions. Identification of the phospholipid-binding subunit and analyses of a two-stage binding process. J. Biol. Chem. 265, 7619–7622 (1990).

    CAS  PubMed  Google Scholar 

  10. Tandan, S. et al. Physical and functional interaction between calcineurin and the cardiac L-type Ca2+ channel. Circ. Res. 105, 51–60 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saito, T. et al. Structure, expression profile, and chromosomal location of a mouse gene homologous to human DNA-PKcs interacting protein (KIP) gene. Mamm. Genome 10, 315–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Shock, D.D. et al. Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton. Biochem. J. 342, 729–735 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stabler, S.M., Ostrowski, L.L., Janicki, S.M. & Monteiro, M.J. A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. J. Cell Biol. 145, 1277–1292 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gentry, H.R. et al. Structural and biochemical characterization of CIB1 delineates a new family of EF-hand–containing proteins. J. Biol. Chem. 280, 8407–8415 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Naik, M.U. & Naik, U.P. Calcium- and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen. Blood 102, 3629–3636 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Haataja, L., Kaartinen, V., Groffen, J. & Heisterkamp, N. The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin αIIbβ3-mediated adhesion and spreading. J. Biol. Chem. 277, 8321–8328 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Leisner, T.M., Liu, M., Jaffer, Z.M., Chernoff, J. & Parise, L.V. Essential role of CIB1 in regulating PAK1 activation and cell migration. J. Cell Biol. 170, 465–476 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Naik, U.P., Patel, P.M. & Parise, L.V. Identification of a novel calcium-binding protein that interacts with the integrin αIIb cytoplasmic domain. J. Biol. Chem. 272, 4651–4654 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Jarman, K.E., Moretti, P.A., Zebol, J.R. & Pitson, S.M. Translocation of sphingosine kinase 1 to the plasma membrane is mediated by calcium and integrin binding protein 1. J. Biol. Chem. 285, 483–492 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Yuan, W. et al. CIB1 is essential for mouse spermatogenesis. Mol. Cell. Biol. 26, 8507–8514 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zayed, M.A. et al. CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis. Circ. Res. 101, 1185–1193 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Sanbe, A. et al. Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ. Res. 92, 609–616 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Molkentin, J.D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bueno, O.F. et al. Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice. Proc. Natl. Acad. Sci. USA 99, 4586–4591 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Häger, M. et al. Cib2 binds integrin α7bβ1d and is reduced in laminin α2 chain-deficient muscular dystrophy. J. Biol. Chem. 283, 24760–24769 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhu, J., Stabler, S.M., Ames, J.B., Baskakov, I. & Monteiro, M.J. Calcium binding sequences in calmyrin regulates interaction with presenilin-2. Exp. Cell Res. 300, 440–454 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Frey, N., Katus, H.A., Olson, E.N. & Hill, J.A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580–1589 (2004).

    Article  PubMed  Google Scholar 

  28. DeBosch, B. et al. Akt1 is required for physiological cardiac growth. Circulation 113, 2097–2104 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Brancaccio, M. et al. Melusin, a muscle-specific integrin β1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat. Med. 9, 68–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Parsons, S.A. et al. Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy. J. Biol. Chem. 279, 26192–26200 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Bourajjaj, M. et al. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J. Biol. Chem. 283, 22295–22303 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Wilkins, B.J. et al. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol. Cell. Biol. 22, 7603–7613 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li, W. & Handschumacher, R.E. Identification of two calcineurin B-binding proteins: tubulin and heat shock protein 60. Biochim. Biophys. Acta 1599, 72–81 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Politino, M. & King, M.M. Calcium- and calmodulin-sensitive interactions of calcineurin with phospholipids. J. Biol. Chem. 262, 10109–10113 (1987).

    CAS  PubMed  Google Scholar 

  35. Iida, T., Egusa, H., Saeki, M., Yatani, H. & Kamisaki, Y. PICK1 binds to calcineurin B and modulates the NFAT activity in PC12 cells. Biochem. Biophys. Res. Commun. 375, 655–659 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Wilkins, B.J. et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ. Res. 94, 110–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Heineke, J. et al. Downregulation of cytoskeletal muscle LIM protein by nitric oxide: impact on cardiac myocyte hypertrophy. Circulation 107, 1424–1432 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Lim, H.W. et al. Calcineurin expression, activation and function in cardiac pressure-overload hypertrophy. Circulation 101, 2431–2437 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Parsons, S.A., Millay, D.P., Sargent, M.A., McNally, E.M. & Molkentin, J.D. Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. Am. J. Pathol. 168, 1975–1985 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hilfiker-Kleiner, D. et al. A cathepsin D–cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128, 589–600 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Haq, S. et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103, 670–677 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, Q., Wilkins, B.J., Lee, Y.J., Ichijo, H. & Molkentin, J.D. Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth. Mol. Cell. Biol. 26, 3785–3797 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vila-Carriles, W.H., Zhou, Z.H., Bubien, J.K., Fuller, C.M. & Benos, D.J. Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. J. Biol. Chem. 282, 34381–34391 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Jernigan, N.L. et al. Dietary salt enhances benzamil-sensitive component of myogenic constriction in mesenteric arteries. Am. J. Physiol. Heart Circ. Physiol. 294, H409–H420 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Kabaeva, Z., Zhao, M. & Michele, D.E. Blebbistatin extends culture life of adult mouse cardiac myocytes and allows efficient and stable transgene expression. Am. J. Physiol. Heart Circ. Physiol. 294, H1667–H1674 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Baines, C.P., Kaiser, R.A., Sheiko, T., Craigen, W.J. & Molkentin, J.D. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. 9, 550–555 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Neilson, J.R., Winslow, M.M., Hur, E.M. & Crabtree, G.R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Oka, T. et al. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation and myocyte viability. Circ. Res. 98, 837–845 (2006).

    Article  CAS  PubMed  Google Scholar 

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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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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.

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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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