肺动脉高压
发病机制
心力衰竭
血流动力学
肺
医学
内科学
免疫染色
下调和上调
内皮功能障碍
转录组
血管阻力
内皮干细胞
心脏病学
病理
生物
基因表达
免疫组织化学
生物化学
基因
体外
作者
Bin Liu,Dan Yi,Shuai Li,Karina Ramirez,Xiaomei Xia,Yukun Cao,Hui Zhao,Ankit Tripathi,Shenfeng Qiu,Mrinalini Kala,Ruslan Rafikov,Haiwei Gu,Vinicio de Jesús Pérez,Sarah-Eve Lemay,Christopher C Glembotski,Kenneth S. Knox,Vladimir V. Kalinichenko,Sébastien Bonnet,Michael B. Fallon,Olivier Boucherat,Zhi Dai
标识
DOI:10.1101/2024.02.11.579846
摘要
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Recent studies showed that FABP4 and FABP5 were expressed in ECs across multiple tissues and circulating FABP4 level was elevated in the PAH patients. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined.FABP4/5 expression was examined in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with idiopathic PAH (IPAH) and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1Tie2Cre (CKO) mice and Egln1Tie2Cre/Fabp4-5-/- (TKO) mice. Bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) analysis were performed to understand the cellular and molecular mechanisms of endothelial FABP4/5 mediated PAH pathogenesis.Both FABP4 and FABP5 were highly induced in ECs of CKO mice and PAECs from IPAH patients, and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and 5 in CKO mice caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure. Fabp4/5 deletion also normalized EC glycolysis, reduced ROS and HIF-2α expression, and decreased aberrant EC proliferation in CKO lungs.PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and hyperproliferation, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
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