Department of Internal Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Department of Internal Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China.
J Adv Res. 2022 Sep;40:197-206. doi: 10.1016/j.jare.2021.11.011. Epub 2021 Nov 26.
Pulmonary hypertension secondary to left heart disease (PH-LHD) is a common and fatal disease. However, no effective therapeutic targets have been identified.
Here, we set out to illustrate the functional role and underlying mechanisms of fatty acid-binding protein 5 (FABP5) in PH-LHD development.
We performed a systematic analysis of datasets GSE84704 and GSE16624 to identify differentially expressed genes and then constructed protein-protein interaction network for significant modules. Potential target genes in the modules were validated by RT-qPCR and western blot in a PH-LHD mouse model. PH-LHD or sham mice were treated with FABP5 antagonist SBFI-26 or DMSO for 28 days. The role of FABP5 on cardiac function was determined by echocardiography, its impact on pulmonary vascular remodelling were evaluated with right heart catheter, histological analysis and western blot. In vitro, primary pulmonary adventitial fibroblasts were used to investigate the pro-fibrotic mechanisms involving in FABP5.
FABP5 was the only one dramatically upregulated along with increased protein expression in the established PH-LHD mouse model. Inhibition of FABP5 by SBFI-26 injection abrogated pulmonary artery remodelling in PH-LHD and improved cardiac function. In vitro, SBFI-26 or FABP5 siRNA blunted the TGF-β1-induced fibrotic response in cultured pulmonary adventitial fibroblasts. Mechanistically, FABP5 knockdown inhibited GSK3β phosphorylation and increased β-catenin phosphorylation. The wnt/β-catenin agonist SKL2001 diminished the antifibrotic effect of FABP5 knockdown on pulmonary adventitial fibroblasts under TGF-β1 stimulation.
FABP5 is an important mediator of pulmonary artery remodelling and a potential therapeutic target for PH-LHD.
左心疾病相关肺动脉高压（PH-LHD）是一种常见且致命的疾病，但目前尚未确定有效的治疗靶点。
本研究旨在阐明脂肪酸结合蛋白 5（FABP5）在 PH-LHD 发展中的功能作用和潜在机制。
我们对数据集 GSE84704 和 GSE16624 进行了系统分析，以鉴定差异表达基因，然后构建了显著模块的蛋白质-蛋白质相互作用网络。在 PH-LHD 小鼠模型中，通过 RT-qPCR 和 Western blot 验证模块中的潜在靶基因。PH-LHD 或假手术（sham）小鼠用 FABP5 拮抗剂 SBFI-26 或 DMSO 处理 28 天。通过超声心动图测定 FABP5 对心功能的作用，通过右心导管、组织学分析和 Western blot 评估其对肺血管重构的影响。体外，原代肺外膜成纤维细胞用于研究涉及 FABP5 的促纤维化机制。
在已建立的 PH-LHD 小鼠模型中，FABP5 是唯一一种表达显著上调且蛋白表达增加的基因。用 SBFI-26 注射抑制 FABP5 可阻断 PH-LHD 中的肺动脉重构并改善心功能。在体外，SBFI-26 或 FABP5 siRNA 可阻断 TGF-β1 诱导的培养肺外膜成纤维细胞的纤维化反应。机制上，FABP5 敲低抑制 GSK3β 磷酸化并增加 β-连环蛋白磷酸化。在 TGF-β1 刺激下，Wnt/β-连环蛋白激动剂 SKL2001 减弱了 FABP5 敲低对肺外膜成纤维细胞的抗纤维化作用。
FABP5 是肺动脉重构的重要介质，也是 PH-LHD 的潜在治疗靶点。
