A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure
A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure
复制标题
一种新型成纤维细胞激活抑制剂减轻心力衰竭患者左室重构并保护心功能
DOI：
10.1152/ajpheart.00603.2017
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发表时间：
2018-09-01
影响因子：
4.8
通讯作者：
Lefer, David T.
中科院分区：
文献类型：
--
作者：
Bradley, Jessica M.;Spaletra, Pablo;Lefer, David T.
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-beta. 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-alpha 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.
