Rzepka Mark F, Raschzok Sonja, Lee Xavier A, Yazaki Kana, Dauz John, Sun Mei, Meister Theo, Nghiem Linda, Kabir Golam, Desjardins Jean-Francois, Kuebler Wolfgang M, Kapus Andras, Connelly Kim A, Friedberg Mark K
Division of Cardiology, Labatt Family Heart Center Toronto, Toronto, Ontario, Canada.
Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Am J Respir Cell Mol Biol. 2025 Feb;72(2):158-168. doi: 10.1165/rcmb.2023-0465OC.
Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions in which 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-β1 signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. In this study, we investigated whether MRTF-A inhibition improves RV profibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure loading. Rats were assigned into either sham or PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75 mg/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 profibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, whereas 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 coactivator 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 transforming growth factor-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of profibrotic signaling in RV pressure loading and as potential targets to improve RV profibrotic remodeling.
在多种右心室压力负荷增加、右心室机械应力升高的情况下，右心室（RV）纤维化与右心室功能障碍相关，但驱动右心室纤维化的潜在机制尚未完全明确。在以机械应力升高和转化生长因子-β1信号传导为特征的肺部和心血管疾病中，心肌相关转录因子A（MRTF-A）是驱动肌成纤维细胞转变和纤维化的关键机械敏感蛋白。在本研究中，我们调查了抑制MRTF-A是否能改善右心室压力负荷的肺动脉环扎（PAB）模型中的右心室促纤维化重塑和功能。将大鼠分为假手术组或PAB组。在一部分PAB动物中，每天给予0.75mg/kg的MRTF-A抑制剂CCG-1423。6周后的终末实验时进行超声心动图和压力-容积血流动力学检测。对右心室心肌样本进行纤维化、心肌细胞肥大和促纤维化信号分析。抑制MRTF-A可使PAB大鼠的收缩功能障碍略有减轻，表现为三尖瓣环外侧收缩期峰值速度增加，而舒张功能参数未得到显著改善。抑制MRTF-A的PAB大鼠右心室重塑减弱，纤维化减少。这伴随着PAB诱导的Yes相关蛋白（YAP）及其同源物具有PDZ结合基序的转录共激活因子（TAZ）上调的减少。我们还使用第二代MRTF-A抑制剂CCG-203971证实，MRTF-A在驱动右心室成纤维细胞表达TAZ以及在转化生长因子-β1应激和RhoA激活时的肌成纤维细胞转变标志物方面起关键作用。这些研究确定RhoA、MRTF-A和YAP/TAZ是右心室压力负荷中促纤维化信号的相互关联调节因子，也是改善右心室促纤维化重塑的潜在靶点。
