Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload

J Clin Invest. 2011 Jun;121(6):2301-12. doi: 10.1172/JCI44824. Epub 2011 May 2.


The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-β, which is generated by and interacts with multiple cell types. Here we have shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-β-neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-β-activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-β type 2 receptor (TβR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TβR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TβR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Diseases / complications
  • Aortic Diseases / physiopathology
  • Bone Morphogenetic Protein 7 / physiology
  • Connective Tissue Growth Factor / physiology
  • Constriction, Pathologic / complications
  • Constriction, Pathologic / physiopathology
  • Coronary Circulation
  • Gene Knockdown Techniques
  • Hypertrophy, Left Ventricular / diagnostic imaging
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / physiopathology*
  • Hypertrophy, Left Ventricular / prevention & control
  • Ligation
  • MAP Kinase Kinase Kinases / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / pathology
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology*
  • Pressure
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / physiology
  • Signal Transduction
  • Smad Proteins / physiology
  • Transforming Growth Factor beta1 / antagonists & inhibitors
  • Transforming Growth Factor beta1 / physiology*
  • Ultrasonography
  • Ventricular Remodeling / physiology*


  • Bone Morphogenetic Protein 7
  • CCN2 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • bmp7 protein, mouse
  • Connective Tissue Growth Factor
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II