Brancaccio Mara, Fratta Luigi, Notte Antonella, Hirsch Emilio, Poulet Roberta, Guazzone Simona, De Acetis Marika, Vecchione Carmine, Marino Gennaro, Altruda Fiorella, Silengo Lorenzo, Tarone Guido, Lembo Giuseppe
Department of Genetics, Biology, and Biochemistry, Turin University, 10126 Turin, Italy.
Nat Med. 2003 Jan;9(1):68-75. doi: 10.1038/nm805. Epub 2002 Dec 23.
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.
心脏肥大是对多种机械和激素刺激的一种适应性反应，是导致心力衰竭临床过程中的早期事件。通过基因失活，我们在此证明了melusin（一种与整合素β1胞质结构域相互作用的肌肉特异性蛋白）在对机械过载的肥大反应中起关键作用。Melusin基因敲除小鼠在生理条件下心脏结构和功能正常，但在承受压力过载（一种在野生型对照中诱导肥大反应的情况）时，它们会出现异常的心脏重塑，进而发展为扩张型心肌病和收缩功能障碍。相比之下，在以不升高血压的剂量长期给予血管紧张素II或去氧肾上腺素后（即在没有心脏生物力学应激的情况下），野生型和Melusin基因敲除小鼠的肥大反应是相同的。对压力过载诱导的细胞内信号事件的分析表明，糖原合酶激酶-3β（GSK-3β）的磷酸化在Melusin基因敲除的心脏中特异性减弱。因此，Melusin通过特异性感知机械应力来防止慢性压力过载期间的心脏扩张。
