TY - JOUR
T1 - Pim-1 regulates cardiomyocyte survival downstream of Akt
AU - Muraski, John A.
AU - Rota, Marcello
AU - Misao, Yu
AU - Fransioli, Jenna
AU - Cottage, Christopher
AU - Gude, Natalie
AU - Esposito, Grazia
AU - Delucchi, Francesca
AU - Arcarese, Michael
AU - Alvarez, Roberto
AU - Siddiqi, Sailay
AU - Emmanuel, Gregory N.
AU - Wu, Weitao
AU - Fischer, Kimberlee
AU - Martindale, Joshua J.
AU - Glembotski, Christopher C.
AU - Leri, Annarosa
AU - Kajstura, Jan
AU - Magnuson, Nancy
AU - Berns, Anton
AU - Beretta, Remus M.
AU - Houser, Steven R.
AU - Schaefer, Erik M.
AU - Anversa, Piero
AU - Sussman, Mark A.
N1 - Funding Information:
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.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/36849037512
UR - https://www.scopus.com/pages/publications/36849037512#tab=citedBy
U2 - 10.1038/nm1671
DO - 10.1038/nm1671
M3 - Article
C2 - 18037896
AN - SCOPUS:36849037512
SN - 1078-8956
VL - 13
SP - 1467
EP - 1475
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -