Protective Roles of Interferon-γ in Cardiac Hypertrophy Induced by Sustained Pressure Overload

J Am Heart Assoc. 2018 Mar 19;7(6):e008145. doi: 10.1161/JAHA.117.008145.

Abstract

Background: A clear understanding of the molecular mechanisms underlying hemodynamic stress-initiated cardiac hypertrophy is important for preventing heart failure. Interferon-γ (IFN-γ) has been suggested to play crucial roles in various diseases other than immunological disorders by modulating the expression of myriad genes. However, the involvement of IFN-γ in the pathogenesis of cardiac hypertrophy still remains unclear.

Methods and results: In order to elucidate the roles of IFN-γ in pressure overload-induced cardiac pathology, we subjected Balb/c wild-type (WT) or IFN-γ-deficient (Ifng-/-) mice to transverse aortic constriction (TAC). Three weeks after TAC, Ifng-/- mice developed more severe cardiac hypertrophy, fibrosis, and dysfunction than WT mice. Bone marrow-derived immune cells including macrophages were a source of IFN-γ in hearts after TAC. The activation of PI3K/Akt signaling, a key signaling pathway in compensatory hypertrophy, was detected 3 days after TAC in the left ventricles of WT mice and was markedly attenuated in Ifng-/- mice. The administration of a neutralizing anti-IFN-γ antibody abrogated PI3K/Akt signal activation in WT mice during compensatory hypertrophy, while that of IFN-γ activated PI3K/Akt signaling in Ifng-/- mice. TAC also induced the phosphorylation of Stat5, but not Stat1 in the left ventricles of WT mice 3 days after TAC. Furthermore, IFN-γ induced Stat5 and Akt phosphorylation in rat cardiomyocytes cultured under stretch conditions. A Stat5 inhibitor significantly suppressed PI3K/Akt signaling activation in the left ventricles of WT mice, and aggravated pressure overload-induced cardiac hypertrophy.

Conclusions: The IFN-γ/Stat5 axis may be protective against persistent pressure overload-induced cardiac hypertrophy by activating the PI3K/Akt pathway.

Keywords: PI3K/Akt; cell signaling; cytokine; hypertrophy; interferon‐γ; protein kinase B; signal transducer and activator of transcription 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Fibrosis
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control*
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Male
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left*
  • Ventricular Remodeling*

Substances

  • IFNG protein, mouse
  • Receptors, Interferon
  • STAT5 Transcription Factor
  • interferon gamma receptor
  • Interferon-gamma
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt