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.
Kuba
Keiji
K
Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria.
Zhang
Liyong
L
Imai
Yumiko
Y
Arab
Sara
S
Chen
Manyin
M
Maekawa
Yuichiro
Y
Leschnik
Michael
M
Leibbrandt
Andreas
A
Markovic
Mato
M
Makovic
Mato
M
Schwaighofer
Julia
J
Beetz
Nadine
N
Musialek
Renata
R
Neely
G Greg
GG
Komnenovic
Vukoslav
V
Kolm
Ursula
U
Metzler
Bernhard
B
Ricci
Romeo
R
Hara
Hiromitsu
H
Meixner
Arabella
A
Nghiem
Mai
M
Chen
Xin
X
Dawood
Fayez
F
Wong
Kit Man
KM
Sarao
Renu
R
Cukerman
Eva
E
Kimura
Akinori
A
Hein
Lutz
L
Thalhammer
Johann
J
Liu
Peter P
PP
Penninger
Josef M
JM
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