Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload.
Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca(2+) transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels.
Muraski
John A
JA
San Diego State Heart Institute, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.
Fischer
Kimberlee M
KM
Wu
Weitao
W
Cottage
Christopher T
CT
Quijada
Pearl
P
Mason
Matt
M
Din
Shabana
S
Gude
Natalie
N
Alvarez
Roberto
R
Rota
Marcello
M
Kajstura
Jan
J
Wang
Zeping
Z
Schaefer
Erik
E
Chen
Xiongen
X
MacDonnel
Scott
S
Magnuson
Nancy
N
Houser
Stephen R
SR
Anversa
Piero
P
Sussman
Mark A
MA
D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000201:enzymology; D017209:Apoptosis; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D005355:Fibrosis; D009119:Muscle Contraction; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D019332:Endothelin-1; D051573:Proto-Oncogene Proteins c-pim-1
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