抑制 MRTF-A 可改善压力负荷右心室的病理重塑。

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mark F Rzepka, Sonja Raschzok, Xavier A Lee, Kana Yazaki, John Dauz, Mei Sun, Theo Meister, Linda Nghiem, Golam Kabir, Jean-Francois Desjardins, Wolfgang M Kuebler, Andras Kapus, Kim A Connelly, Mark K Friedberg
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引用次数: 0

摘要

在各种右心室压力负荷条件下,右心室纤维化与右心室功能障碍有关,在这些条件下,右心室机械应力增加,但驱动右心室纤维化的潜在机制尚不完全清楚。在以机械应力升高和转化生长因子-β-1(TGF-β1)信号传导为特征的肺部和心血管疾病中,心肌蛋白相关转录因子 A(MRTF-A)是一种机械敏感蛋白,对驱动肌成纤维细胞转化和纤维化至关重要。在此,我们研究了抑制MRTF-A是否能改善肺动脉束带(PAB)模型RV压力负荷下的RV促纤维化重塑和功能。大鼠被分配到 1) 假组或 2) PAB 组。在PAB动物中,每天以0.75毫克/千克的剂量给药MRTF-A抑制剂CCG-1423。在 6 周后的终末实验中进行超声心动图检查和压力-容积血流动力学检查。对 RV 心肌样本进行了纤维化、心肌细胞肥大和促纤维化信号传导分析。MRTF-A抑制可轻微减轻PAB大鼠的收缩功能障碍,表现为三尖瓣环外侧峰值收缩速度增加,而舒张功能参数没有明显改善。MRTF-A抑制剂减轻了PAB大鼠的RV重塑,减少了纤维化。与此同时,PAB 诱导的是相关蛋白(YAP)及其具有 PDZ 结合基调的同系物转录共激活因子(TAZ)的上调也有所降低。我们还使用第二代MRTF-A抑制剂CCG-203971证实,MRTF-A在响应TGF-β1压力和RhoA激活时对驱动RV成纤维细胞表达TAZ和肌成纤维细胞转化标记物至关重要。这些研究发现,RhoA、MRTF-A 和 YAP/TAZ 是 RV 压力负荷下促纤维化信号转导的相互关联的调节因子,也是改善 RV 促纤维化重塑的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of MRTF-A Ameliorates Pathological Remodeling of the Pressure-loaded Right Ventricle.

Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions where RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor - beta-1 (TGF-β1) signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. Here we investigated whether MRTF-A inhibition improves RV pro-fibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure-loading. Rats were assigned into either 1) sham or 2) PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6-weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and pro-fibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, while diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ). We also confirmed using a second-generation MRTF-A inhibitor CCG-203971 that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to TGF-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and as potential targets to improve RV pro-fibrotic remodeling.

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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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