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Small molecule Gβγ inhibition reduces pathologic activation of cardiac fibroblasts (LB563)
Author(s) -
Travers Joshua,
Kamal Fadia,
Blaxall Burns
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb563
Subject(s) - protein kinase b , fibrosis , angiotensin ii , downregulation and upregulation , pi3k/akt/mtor pathway , heart failure , inflammation , cardiac fibrosis , chemistry , phosphoinositide 3 kinase , beta adrenergic receptor kinase , cancer research , phosphorylation , kinase , endocrinology , muscle hypertrophy , signal transduction , receptor , medicine , microbiology and biotechnology , biology , g protein coupled receptor , biochemistry , gene
Heart failure (HF) is a devastating disease characterized by cardiac hypertrophy, fibrosis and inflammation. Excess signaling through Gβγ subunits leads to chronic β‐adrenergic receptor (β‐AR) downregulation, mediated predominantly by β‐AR kinase 1 (GRK2) in complex with phosphoinositide 3 kinase γ (PI3Kγ). Our recent work has demonstrated the therapeutic potential of the small molecule Gβγ‐GRK2 inhibitor Gallein in limiting HF progression. Chronic activation of cardiac fibroblasts (CF), critical yet underappreciated myocardial cells, is a key contributor to pathologic cardiac remodeling. We hypothesized that Gβγ‐GRK2 inhibition may limit pathologic CF activation. CFs were stimulated with Isoproterenol (Iso, β‐AR agonist) or Angiotensin II +/‐ Gallein for 24hr. Gallein treatment attenuated the induction in the expression of α smooth muscle actin (αSMA), a marker of pathologic CF activation, several inflammatory cytokines and collagen, as assessed by qRT‐PCR. Gβγ inhibition also mitigated the induction in the phosphorylation of Akt, a kinase downstream of PI3Kγ, in both rodent and failing human CFs. We have recently demonstrated that the protease‐activated receptor 1 (PAR1), a GPCR we have implicated in cardiac hypertrophy, is pathologically transactivated via chronic β‐AR stimulation by induction of MMP‐13, a protease we have found to be elevated in HF. Interestingly, Gβγ inhibition reduced PAR1 cleavage in response to chronic Iso. In summary, small molecule Gβγ inhibition appears to reduce pathologic CF activation, and the reduction in β‐AR‐mediated PAR1 cleavage reveals an alternative mechanism for Gβγ inhibition. These data suggest a potential therapeutic role for small molecule Gβγ inhibition in limiting pathologic CF activation and HF progression. Grant Funding Source : Supported by the Pharmaceutical Research and Manufacturers of America Foundation