A Novel Fibroblast Activation Inhibitor Attenuates Left Ventricular Remodeling and Preserves Cardiac Function in Heart Failure
Jessica M Bradley, Pablo Spaletra, Zhen Li, Thomas E. Sharp, Traci T Goodchild, Laura G. Corral, Leah Fung, Kyle W. Chan, Robert W. Sullivan, Cathy A. Swindlehurst, David J. LeferAmerican Journal of Physiology-Heart and Circulatory Physiology2018
BACKGROUND: Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of pro-fibrotic factors such as TGF-β. Myocardial fibrosis worsens cardiac function accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (i.e., NM922, NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload induced HF. RESULTS: NM922 inhibited fibroblasts- myofibroblasts transformation in vitro via reducing the activation of FAK-Akt-P70S6K and STAT3/4E-BP1 pathway as well as via induction of COX-2. NM922 preserved left ventricular (LV) ejection fraction (p < 0.05 vs. VEH) and significantly attenuated TAC-induced LV dilation and hypertrophy (p < 0.05 compared to VEH). NM922 significantly (p < 0.05) inhibited fibroblast activation as evidenced by reduced myofibroblast counts per mm2 tissue area. Picrosirus Red staining demonstrated that NM922 reduced (p < 0.05) interstitial fibrosis compared to mice receiving Vehicle (VEH). Similarly, NM922 hearts had lower mRNA levels (p < 0.05) of collagen I and III, lysyl oxidase, and tumor necrosis factor (TNF) at 16 wks post-TAC. CONCLUSION: Treatment with NM922 following the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of LVEF. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel anti-fibrotic agent protects the failing heart.