A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

Abstract

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

“…Many researchers are now focusing on the possible inhibition of pro-fibrotic signaling and the activation of antifibrotic pathways [ 1 ]. Promising results have been achieved, but, at least for now, they are limited to animal models or in vitro analyses [ 34 , 38 , 144 , 145 , 146 ]. Beneficial effects of some antifibrotic therapies have been observed in clinical studies on humans, but the population investigated is still too small [ 29 , 147 ] and the possibility of translating animal results to human patients is hampered by the obvious physiologic and genetic differences between them [ 29 , 148 ].…”

Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a 68Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04

“…Identification of drugs that selectively inhibit fibroblast activation and transdifferentiation to the ECM-secreting myofibroblast cell state represents an attractive approach to the treatment of fibrosis-related diseases, which include not only MI but also other common diseases such as liver cirrhosis or pulmonary fibrosis (12). Antifibrotic treatments inhibiting the pathways responsible for interconversion of quiescent fibroblasts to activated and profibrotic myofibroblasts have shown promise for improving left ventricular function in preclinical studies (13)(14)(15). However, translation of experimental findings into human patients has been rather limited.…”

The Roles of Noncardiomyocytes in Cardiac Remodeling

“…A bFGF-encapsulating hydrogel not only served as a drug carrier, but also effectively preserved fibroblast phenotypes so that the pro-angiogenesis and anti-fibrotic functions of CFs were maintained 39 . Additionally, some cardioprotective molecules associated with CFs have been discovered, for example, a novel agent, NM922, of therapeutic value could inhibit the conversion of the CF phenotype in a murine TAC model by preventing the activation of several profibrotic pathways (including pathways involving mTOR/STAT3/E4-BP1, FAK-Akt-P70S6K, and the generation of COX-2) 40 . Administration of sacubitril/valsartan (SAC/VAL) appears to be a promising strategy to improve pressure overload-induced cardiac fibrosis by directly acting on fibroblasts.…”