Cellular and functional defects in a mouse model of heart failure.
Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP(-/-)). The character and extent of the heart failure that occurs in MLP(-/-) mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP(-/-) mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP(-/-) mice were examined in isolated single cells using patch-clamp and confocal Ca(2+) concentration ([Ca(2+)]) imaging techniques. This cellular investigation revealed unchanged Ca(2+) currents and Ca(2+) spark characteristics but decreased intracellular [Ca(2+)] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP(-/-) mice that express a cardiac-targeted transgene, which blocks the function of beta-adrenergic receptor (beta-AR) kinase-1 (betaARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP(-/-) mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the beta-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of betaARK1 action may prove an effective therapy for heart failure.
Esposito
G
G
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Santana
L F
LF
Dilly
K
K
Cruz
J D
JD
Mao
L
L
Lederer
W J
WJ
Rockman
H A
HA
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002306:Cardiac Volume / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013599:Systole / Q000502:physiology; D019076:Transgenes / Q000502:physiology; D017725:Ventricular Pressure / Q000502:physiology; D051552:beta-Adrenergic Receptor Kinases
D060588:LIM Domain Proteins; D009124:Muscle Proteins; D011943:Receptors, Adrenergic, beta; C090114:cysteine and glycine-rich protein 3; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases