Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload.

Abstract

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.

• Authors: Mara Brancaccio, Luigi Fratta, Antonella Notte, Emilio Hirsch, Roberta Poulet, Simona Guazzone, Marika De Acetis, Carmine Vecchione, Gennaro Marino, Fiorella Altruda, Lorenzo Silengo, Guido Tarone, Giuseppe Lembo
• Journal: Nature medicine (Nat Med) Vol. 9 Issue 1 Pg. 68-75 (Jan 2003) ISSN: 1078-8956 [Print] United States
• PMID: 12496958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cytoskeletal Proteins
• ITGB1BP2 protein, human
• Integrin beta1
• Itgb1bp2 protein, mouse
• Muscle Proteins
• Vasoconstrictor Agents
• Angiotensin II
• Phenylephrine

Topics

• Angiotensin II (pharmacology)
• Animals
• Aortic Coarctation
• Biomechanical Phenomena
• Cardiac Output, Low
• Cardiomegaly
• Carrier Proteins (genetics, metabolism)
• Cytoskeletal Proteins
• Echocardiography
• Female
• Gene Silencing
• Heart Ventricles (anatomy & histology, drug effects, pathology)
• Hemodynamics
• Integrin beta1 (metabolism)
• Male
• Mice
• Mice, Knockout
• Muscle Proteins (genetics, metabolism)
• Muscle, Skeletal (cytology, physiology)
• Myocardium (cytology, metabolism)
• Phenylephrine (pharmacology)
• Signal Transduction (physiology)
• Stress, Mechanical
• Vasoconstrictor Agents (pharmacology)
• Ventricular Function