Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload.
Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.
Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria.
Keiji
K
Kuba
Liyong
L
Zhang
Yumiko
Y
Imai
Sara
S
Arab
Manyin
M
Chen
Yuichiro
Y
Maekawa
Michael
M
Leschnik
Andreas
A
Leibbrandt
Mato
M
Markovic
Mato
M
Makovic
Julia
J
Schwaighofer
Nadine
N
Beetz
Renata
R
Musialek
G Greg
GG
Neely
Vukoslav
V
Komnenovic
Ursula
U
Kolm
Bernhard
B
Metzler
Romeo
R
Ricci
Hiromitsu
H
Hara
Arabella
A
Meixner
Mai
M
Nghiem
Xin
X
Chen
Fayez
F
Dawood
Kit Man
KM
Wong
Renu
R
Sarao
Eva
E
Cukerman
Akinori
A
Kimura
Lutz
L
Hein
Johann
J
Thalhammer
Peter P
PP
Liu
Josef M
JM
Penninger
D054392:Adipokines; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001011:Aorta; D000073861:Apelin; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004327:Drinking Behavior; D004452:Echocardiography; D005247:Feeding Behavior; D005260:Female; D006321:Heart / Q000196:embryology / Q000502:physiology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index
D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger