Pim-1 regulates cardiomyocyte survival downstream of Akt

John A. Muraski, Marcello Rota, Yu Misao, Jenna Fransioli, Christopher Cottage, Natalie Gude, Grazia Esposito, Francesca Delucchi, Michael Arcarese, Roberto Alvarez, Sailay Siddiqi, Gregory N. Emmanuel, Weitao Wu, Kimberlee Fischer, Joshua J. Martindale, Christopher C. Glembotski, Annarosa Leri, Jan Kajstura, Nancy Magnuson, Anton BernsRemus M. Beretta, Steven R. Houser, Erik M. Schaefer, Piero Anversa, Mark A. Sussman

Research output: Contribution to journalArticlepeer-review

192 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1467-1475
Number of pages9
JournalNature Medicine
Volume13
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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