Pim-1 regulates cardiomyocyte survival downstream of Akt

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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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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