Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart.
Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient mice develop striking cardiac hypertrophy and die prematurely. Whether their cardiac changes are caused primarily by GLUT4 deficiency in cardiomyocytes or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle and adipose tissue is unclear. To determine the role of GLUT4 in the heart we used cre-loxP recombination to generate G4H(-/-) mice in which GLUT4 expression is abolished in the heart but is present in skeletal muscle and adipose tissue. Life span and serum concentrations of insulin, glucose, FFAs, lactate, and beta-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1 expression were both increased approximately 3-fold in G4H(-/-) mice, but insulin-stimulated glucose uptake was abolished. G4H(-/-) mice develop modest cardiac hypertrophy associated with increased myocyte size and induction of atrial natriuretic and brain natriuretic peptide gene expression in the ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated isovolumic contractile performance was preserved. Thus, selective ablation of GLUT4 in the heart initiates a series of events that results in compensated cardiac hypertrophy.
Abel
E D
ED
Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. dabel@caregroup.harvard.edu
Kaulbach
H C
HC
Tian
R
R
Hopkins
J C
JC
Duffy
J
J
Doetschman
T
T
Minnemann
T
T
Boers
M E
ME
Hadro
E
E
Oberste-Berghaus
C
C
Quist
W
W
Lowell
B B
BB
Ingwall
J S
JS
Kahn
B B
BB
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D009929:Organ Size
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D005947:Glucose