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Impaired JAK2-induced activation of STAT3 in failing human myocytes

Giulia Elisa Cambi1, Gianluca Lucchese, Mah Mc Harol Djeokeng

  • 1Department of Critical Care Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.

Molecular Biosystems
|June 28, 2012
PubMed

Insights

In human heart failure, angiotensin II triggers pro-inflammatory Janus-activated kinase 2 (JAK2) pathways in cardiomyocytes, unlike in non-failing hearts. This altered JAK2-STATs signaling may drive cardiac dysfunction progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cell Signaling

Background:

  • Angiotensin II (Ang II) signaling is implicated in heart failure.
  • Janus-activated kinase 2 (JAK2) phosphorylation is elevated in failing human cardiomyocytes.
  • The downstream effects of JAK2 activation on signal transducer and activator of transcription (STATs) in failing hearts are not well understood.

Purpose of the Study:

  • To investigate STATs phosphorylation and gene expression following JAK2 activation in human failing and non-failing cardiomyocytes.
  • To elucidate the downstream signaling pathways modulated by JAK2 in cardiac dysfunction.

Main Methods:

  • Isolated cardiomyocytes from human failing (n=16) and non-failing (n=6) hearts, and adult rats were treated with Ang II.
  • Phosphorylation of STAT2, STAT3, and STAT5 was assessed.
  • Expression of B-cell lymphoma-extra large (Bcl-xL) and Fas ligand (Fas-L) genes was quantified.
  • JAK2, extracellular signal-regulated kinase (ERK)1/2, and p38 mitogen-activated protein kinase (MAPK) inhibitors were used to probe signaling pathways.

Main Results:

  • In non-failing myocytes, Ang II induced JAK2 activation, leading to STAT3 phosphorylation and Bcl-xL overexpression, modulated by JAK2/ERK1/2.
  • Fas ligand response in non-failing myocytes was inhibited by p38MAPK antagonism.
  • In failing myocytes, Ang II induced JAK2 activation resulted in STAT2 and STAT5 phosphorylation, with no STAT3 response.
  • Failing myocytes showed Fas-L gene overexpression, inhibited by p38MAPK antagonism, but no changes in Bcl-xL.
  • The altered JAK2-induced STATs response was observed in failing human cardiomyocytes.

Conclusions:

  • Human failing cardiomyocytes exhibit a distinct Ang II-induced JAK2-STATs signaling profile compared to non-failing cells, favoring pro-inflammatory STAT2/STAT5 over cardio-protective STAT3.
  • This aberrant signaling pathway involving JAK2 and STATs may contribute to the progression of cardiac dysfunction in heart failure.
  • Targeting specific components of this pathway could offer therapeutic potential for heart failure management.

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