βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

JCI Insight. 2019 Oct 17;4(20):e131046. doi: 10.1172/jci.insight.131046.

Abstract

Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of βIV-spectrin deficiency. Loss of βIV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in βIV-spectrin-deficient fibroblasts by expressing a βIV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global βIV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of βIV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the βIV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).

Keywords: Cardiology; Cell Biology; Cytoskeleton; Fibrosis; Heart failure.

Publication types

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

MeSH terms

  • Animals
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / pathology
  • Cardiovascular Diseases / physiopathology*
  • Disease Models, Animal
  • Female
  • Fibroblasts / pathology*
  • Fibrosis
  • Heart Ventricles / cytology
  • Heart Ventricles / pathology*
  • Heart Ventricles / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism*
  • Spectrin / deficiency*
  • Spectrin / genetics
  • Ventricular Remodeling

Substances

  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • betaIV spectrin, mouse
  • Spectrin