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Poster Abstract PresentationsSession Title: Poster Session 3

Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling

Joshua G Travers, Fadia A Kamal, Michael S Burhans, Burns C Blaxall
Circulation Research. 2014;115:A319
Joshua G Travers
Cincinnati Children's Hosp Med Cntr, Cincinnati, OH
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Fadia A Kamal
Cincinnati Children's Hosp Med Cntr, Cincinnati, OH
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Michael S Burhans
Cincinnati Children's Hosp Med Cntr, Cincinnati, OH
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Burns C Blaxall
Cincinnati Children's Hosp Med Cntr, Cincinnati, OH
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Abstract

Heart failure (HF) is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Prolonged sympathetic overstimulation promotes excess signaling through G-protein Gβγ subunits and ultimately results in pathologic GRK2-mediated β-adrenergic receptor (β-AR) downregulation. We have recently demonstrated the therapeutic potential of the small molecule Gβγ-GRK2 inhibitor Gallein in limiting HF progression. Pathologic activation of the cardiac fibroblast (CF) induces the transition to a myofibroblast phenotype, which plays a fundamental role in myocardial fibrosis and remodeling. We hypothesized that Gβγ-GRK2 inhibition plays an important functional role in the CF to attenuate pathologic CF activation, inflammation and interstitial fibrosis.

To explore the effect of Gβγ-GRK2 inhibition on inflammation and pro-fibrotic signaling, mice were subjected to 7 days of transverse aortic constriction, a pressure-overload model of HF. In addition to the attenuation in overall cardiac hypertrophy, animals treated with Gallein displayed reduced expression of pro-inflammatory cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α) and MIP-1β, along with Interleukin-6, as assessed by qPCR. Gallein-treated animals also exhibited diminished pro-fibrotic signaling, as evidenced by a reduction in the expression of TGFβ, a major driver of myocardial fibrosis, and decreased expression of collagen. To recapitulate these findings in vitro, primary adult mouse ventricular fibroblasts were pathologically stimulated using Isoproterenol (ISO, β-AR agonist) or Angiotensin II and treated +/- Gallein for 24 hours. CFs treated with Gallein displayed an analogous reduction in the expression of these pro-inflammatory cytokines and collagen.

In summary, these data suggest a potential therapeutic role for small molecule Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, inflammation and interstitial fibrosis. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of HF.

  • Fibrosis
  • Inflammation
  • Heart failure
  • Author Disclosures: J.G. Travers: None F.A. Kamal: None M.S. Burhans: None B.C. Blaxall: None.

  • © 2014 by American Heart Association, Inc.
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July 18, 2014, Volume 115, Issue Suppl 1
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    Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling
    Joshua G Travers, Fadia A Kamal, Michael S Burhans and Burns C Blaxall
    Circulation Research. 2014;115:A319, originally published November 6, 2014

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    Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling
    Joshua G Travers, Fadia A Kamal, Michael S Burhans and Burns C Blaxall
    Circulation Research. 2014;115:A319, originally published November 6, 2014
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