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Melusin, a muscle-specific integrin β1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload
被引:230
作者:
Brancaccio, M
Fratta, L
Notte, A
Hirsch, E
Poulet, R
Guazzone, S
De Acetis, M
Vecchione, C
Marino, G
Altruda, F
Silengo, L
Tarone, G
[1
]
Lembo, G
机构:
[1] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy
[2] IRCCS Neuromed, Dept Angiocardioneurol, I-86077 Pozzilli, IS, Italy
[3] San Giovanni Battista Hosp, Expt Med Res Ctr, I-10126 Turin, Italy
[4] Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy
关键词:
D O I:
10.1038/nm805
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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 1 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 wildtype 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.
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页码:68 / 75
页数:8
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