Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload.
Cardiac hypertrophy is an adaptive response to a variety of mechanical and hormonal stimuli, and represents an early event in the clinical course leading to heart failure. By gene inactivation, we demonstrate here a crucial role of melusin, a muscle-specific protein that interacts with the integrin beta1 cytoplasmic domain, in the hypertrophic response to mechanical overload. Melusin-null mice showed normal cardiac structure and function in physiological conditions, but when subjected to pressure overload--a condition that induces a hypertrophic response in wild-type controls--they developed an abnormal cardiac remodeling that evolved into dilated cardiomyopathy and contractile dysfunction. In contrast, the hypertrophic response was identical in wild-type and melusin-null mice after chronic administration of angiotensin II or phenylephrine at doses that do not increase blood pressure--that is, in the absence of cardiac biomechanical stress. Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was specifically blunted in melusin-null hearts. Thus, melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress.
Brancaccio
Mara
M
Department of Genetics, Biology, and Biochemistry, Turin University, 10126 Turin, Italy.
Fratta
Luigi
L
Notte
Antonella
A
Hirsch
Emilio
E
Poulet
Roberta
R
Guazzone
Simona
S
De Acetis
Marika
M
Vecchione
Carmine
C
Marino
Gennaro
G
Altruda
Fiorella
F
Silengo
Lorenzo
L
Tarone
Guido
G
Lembo
Giuseppe
G
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001017:Aortic Coarctation; D001696:Biomechanical Phenomena; D002303:Cardiac Output, Low; D006332:Cardiomegaly; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004452:Echocardiography; D005260:Female; D020868:Gene Silencing; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology; D006439:Hemodynamics; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016276:Ventricular Function
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C492400:ITGB1BP2 protein, human; D019012:Integrin beta1; C122158:Itgb1bp2 protein, mouse; D009124:Muscle Proteins; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine