School of Basic Medical Sciences, Yanbian University, Yanji, 133000, China.
Department of Pulmonary and Critical Care Medicine, Beijing Chaoyang Hospital Affiliated to the Capital Medical University, Beijing, 100020, China.
Sci Rep. 2024 Jun 3;14(1):12716. doi: 10.1038/s41598-024-62900-8.
To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that "extracellular matrix organization" ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMPs expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation.
为了探索肺动脉高压（PAH）的分子发病机制并确定潜在的治疗靶点，我们对缺氧诱导的肺动脉高压小鼠的肺组织进行了转录组测序。我们的基因本体分析显示，“细胞外基质组织”在生物学过程类别中排名较高，基质金属蛋白酶（MMPs）和其他蛋白酶也在其中发挥了重要作用。此外，与常氧组相比，我们证实缺氧组 MMPs 的表达上调，而关键基因 Timp1 下调。我们发现藏红花酸（一种天然的 MMP 抑制剂）可减轻炎症、降低 MMPs 水平、增加 Timp1 表达水平，并减轻缺氧诱导的小鼠肺动脉高压。此外，使用单细胞 RNAseq 数据集分析人类肺细胞图谱中 MMPs 和 Timp1 的细胞分布表明，MMPs 和 Timp1 主要在成纤维细胞群体中表达。此外，体外实验表明藏红花酸可显著抑制肌成纤维细胞增殖、迁移和细胞外基质沉积。此外，我们证明藏红花酸通过抑制 TGF-β1/Smad3 信号通路抑制 TGF-β1 诱导的成纤维细胞活化，并调节肺动脉成纤维细胞 MMP2/TIMP1 平衡，从而抑制缺氧诱导的肺动脉高压。综上所述，我们的结果表明，藏红花酸通过抑制 TGF-β1 诱导的肌成纤维细胞活化来减轻缺氧诱导的小鼠肺动脉高压。
