Pim-1 regulates cardiomyocyte survival downstream of Akt.
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-X(L) 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.
John A
JA
Muraski
Marcello
M
Rota
Yu
Y
Misao
Jenna
J
Fransioli
Christopher
C
Cottage
Natalie
N
Gude
Grazia
G
Esposito
Francesca
F
Delucchi
Michael
M
Arcarese
Roberto
R
Alvarez
Sailay
S
Siddiqi
Gregory N
GN
Emmanuel
Weitao
W
Wu
Kimberlee
K
Fischer
Joshua J
JJ
Martindale
Christopher C
CC
Glembotski
Annarosa
A
Leri
Jan
J
Kajstura
Nancy
N
Magnuson
Anton
A
Berns
Remus M
RM
Beretta
Steven R
SR
Houser
Erik M
EM
Schaefer
Piero
P
Anversa
Mark A
MA
Sussman
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D051020:bcl-X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; C496637:Pim1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1