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Pim-1 regulates cardiomyocyte survival downstream of Akt

Nature Medicine volume 13, pages 1467–1475 (2007)Cite this article

A Corrigendum to this article was published on 01 March 2008

Abstract

The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1–deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-XL protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1–overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1–deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.

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Figure 1: Pim-1 is expressed in the human and mouse myocardium.
Figure 2: Pim-1 induces expression of antiapoptotic proteins and protects against apoptosis.
Figure 3: Cardioprotective stimuli induce Pim-1 expression.
Figure 4: Expression of Pim-1 is Akt dependent.
Figure 5: Pim-1 protects against infarction injury.
Figure 6: Pim-1 expression is necessary to maintain efficient calcium handling.

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Acknowledgements

This work was supported by US National Institutes of Health grants (5R01HL067245, 1R01HL091102 and 1P01HL085577) to M.A.S. and a US National Heart, Lung, and Blood Institute grant 1P01AG023071 to P.A. J.A.M. and N.G. are Fellows of the Rees-Stealy Research Foundation and the San Diego State University Heart Institute. We appreciate the contribution of P. Bonine for outstanding administrative assistance.

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  1. San Diego State University Heart Institute, San Diego State University, 5500 Campanile Drive, San Diego, 92182, California, USA

    John A Muraski, Jenna Fransioli, Christopher Cottage, Natalie Gude, Roberto Alvarez, Sailay Siddiqi, Gregory N Emmanuel, Weitao Wu, Kimberlee Fischer, Joshua J Martindale, Christopher C Glembotski & Mark A Sussman

  2. Cardiovascular Research Institute, New York Medical College, Vosburgh Pavilion, Valhalla, New York, 10595, USA

    Marcello Rota, Yu Misao, Grazia Esposito, Francesca Delucchi, Michael Arcarese, Annarosa Leri, Jan Kajstura & Piero Anversa

  3. School of Molecular Biosciences, Washington State University, Pullman, 99164, Washington, USA

    Nancy Magnuson

  4. Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Anton Berns

  5. Cardiovascular Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, 19140, Pennsylvania, USA

    Remus M Beretta & Steven R Houser

  6. BioSource Cytokines & Signaling, Invitrogen Corporation 94 South Street, Hopkinton, 01748, Maryland, USA

    Erik M Schaefer

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Contributions

J.A.M. planned and performed experiments and wrote the manuscript; M.R. and Y.M. planned and performed experiments; J.F., C.C., G.E., F.D., M.A., R.A. and S.S. performed experiments; G.N.E. and W.W. performed surgeries; K.F., J.J.M., C.C.G., A.L. and J.K. performed experiments and advised on the experimental approach; N.M. provided Pim1 cDNAs and advised on the technical proposal; A.B. provided Pim-KO animals; R.M.B. and S.R.H. provided human samples and advice; E.M.S. provided technical advice and advice on the experimental approach; P.A. provided advice on the experimental approach, rewriting and editing, and laboratory resources for experiments; M.A.S. supervised all experimental procedures and edited and composed the manuscript.

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Correspondence to Mark A Sussman.

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Muraski, J., Rota, M., Misao, Y. et al. Pim-1 regulates cardiomyocyte survival downstream of Akt. Nat Med 13, 1467–1475 (2007). https://doi.org/10.1038/nm1671

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