BET inhibitor apabetalone suppresses the fibrotic activation of cardiac fibroblasts associated with heart dysfunction.

BACKGROUND: Accumulation of extracellular matrix (ECM) causes tissue fibrosis that contributes to myocardial dysfunction and heart failure (HF), yet there are no approved anti-fibrotic therapeutics that target it. Inhibitors of BET proteins (BETi) reduced fibrosis in preclinical HF models, and clinical-stage BETi, apabetalone, reduced hospitalizations for HF in a phase 3 trial, but our mechanistic understanding is incomplete. Here we tested apabetalone for anti-fibrotic activity in cell models that recapitulate cardiac fibrosis. METHODS: Human immortalized cardiac fibroblasts (IM-FBs), cryopreserved cardiac FBs, and ex vivo cultured FBs from patients undergoing bypass grafting surgery were stimulated with profibrotic cytokines TGF-β and IL-1β to elicit changes in gene and protein expression that accompany the profibrotic phenotype. Cell contraction was characterized in collagen gels. RESULTS: In IM-FBs, apabetalone downregulated TGF-β-induced expression of ECM components and regulators. Concordantly, expression of α-smooth muscle actin (α-SMA) and in-gel cell contraction were reduced. TGF-β and IL-1β combination leads to profibrotic activation of primary FBs, as evidenced by elevated α-SMA, changes in morphology, increased contraction and ECM production. In dual cytokine-stimulated primary FBs, apabetalone reduced nuclear localization of the master profibrotic transcription factor MEOX1, and expression of its target gene, periostin. Both prophylactic and therapeutic treatments with apabetalone decreased hallmarks of FB activation. Finally, ex vivo apabetalone treatment reduced in-gel contraction of cardiac FBs obtained from surgical patients with severe cardiovascular disease. CONCLUSIONS: Apabetalone reduced cytokine-mediated profibrotic FB activation in vitro and ex vivo, demonstrating therapeutic potential for adverse cardiac remodeling that contributes to cardiac dysfunction and HF.