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

Nat Med. 2003 Jan;9(1):68-75. doi: 10.1038/nm805. Epub 2002 Dec 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Grant support