Article abstract
Nature Medicine 13, 1467 - 1475 (2007)
Published online: 25 November 2007 | doi:10.1038/nm1671
There is a Corrigendum (March 2008) associated with this Article.
Pim-1 regulates cardiomyocyte survival downstream of Akt
John A Muraski1, Marcello Rota2, Yu Misao2, Jenna Fransioli1, Christopher Cottage1, Natalie Gude1, Grazia Esposito2, Francesca Delucchi2, Michael Arcarese2, Roberto Alvarez1, Sailay Siddiqi1, Gregory N Emmanuel1, Weitao Wu1, Kimberlee Fischer1, Joshua J Martindale1, Christopher C Glembotski1, Annarosa Leri2, Jan Kajstura2, Nancy Magnuson3, Anton Berns4, Remus M Beretta5, Steven R Houser5, Erik M Schaefer6, Piero Anversa2 & Mark A Sussman1
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.
- San Diego State University Heart Institute, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA.
- Cardiovascular Research Institute, New York Medical College, Vosburgh Pavilion, Valhalla, New York 10595, USA.
- School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA.
- Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
- Cardiovascular Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, Pennsylvania 19140, USA.
- BioSource Cytokines & Signaling, Invitrogen Corporation 94 South Street, Hopkinton, Maryland 01748, USA.
Correspondence to: Mark A Sussman1 e-mail: sussman@heart.sdsu.edu
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