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.
Muraski
John A
JA
San Diego State University Heart Institute, San Diego State University, 5500 Campanile Drive, San Diego, California 92182, USA.
Rota
Marcello
M
Misao
Yu
Y
Fransioli
Jenna
J
Cottage
Christopher
C
Gude
Natalie
N
Esposito
Grazia
G
Delucchi
Francesca
F
Arcarese
Michael
M
Alvarez
Roberto
R
Siddiqi
Sailay
S
Emmanuel
Gregory N
GN
Wu
Weitao
W
Fischer
Kimberlee
K
Martindale
Joshua J
JJ
Glembotski
Christopher C
CC
Leri
Annarosa
A
Kajstura
Jan
J
Magnuson
Nancy
N
Berns
Anton
A
Beretta
Remus M
RM
Houser
Steven R
SR
Schaefer
Erik M
EM
Anversa
Piero
P
Sussman
Mark A
MA
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