期刊
NATURE MEDICINE
卷 9, 期 1, 页码 68-75出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm805
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资金
- Telethon [1327] Funding Source: Medline
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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