ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene

Hum Mol Genet. 2016 Jun 1;25(11):2220-2233. doi: 10.1093/hmg/ddw090. Epub 2016 Apr 30.


Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.

MeSH terms

  • Animals
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / pathology
  • Connective Tissue Growth Factor / genetics*
  • Fibrosis / genetics*
  • Fibrosis / pathology
  • Humans
  • Lamin Type A / genetics*
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocardium / pathology
  • Smad Proteins / genetics
  • Transforming Growth Factor beta / genetics*
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / pathology


  • CCN2 protein, mouse
  • Lamin Type A
  • Lmna protein, mouse
  • Smad Proteins
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor