Abstract:
Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53-P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.
摘要:
肺动脉高压(PAH)是一种高发病率和高死亡率的致命疾病。尽管虫草素以其抗炎作用而闻名,抗氧化和免疫增强作用,其在PAH治疗中的作用和潜在机制尚不清楚.使用野百合碱(MCT)诱导的大鼠模型研究了虫草素对PAH大鼠的治疗作用。根据血浆代谢组评估虫草素的代谢作用。通过转录组测序研究了虫草素在PAH治疗中的潜在机制,并在肺动脉平滑肌细胞(PASMC)中进行了验证。评估包括苏木精和伊红染色对肺血管重塑,CCK-8测定,EDU,和细胞活力的TUNEL试剂盒,扩散,和细胞凋亡,分别,蛋白质表达的蛋白质印迹。虫草素显著降低PAH大鼠右心室收缩压(RVSP)和右心室肥厚指数(RVHI),减轻肺血管重塑。血浆代谢组学显示虫草素可以逆转MCT诱导的PAH大鼠肺部代谢紊乱,特别影响亚油酸和α-亚麻酸代谢途径。转录组学显示,P53途径可能是涉及的主要途径,Westernblot结果显示,虫草素显著增加肺组织中P53和P21蛋白水平。转录组学和代谢组学的综合分析表明,这些途径主要富集在亚油酸代谢和α-亚麻酸代谢途径中。体外实验表明,虫草素显著抑制PDGFBB(PD)诱导的PASMC异常增殖和迁移,促进PD诱导的细胞凋亡。同时,冬虫夏草素增强PD损伤的PASMC中P53和P21蛋白的表达水平。然而,P53和P21的抑制剂消除了虫草素的这些作用。虫草素可能通过激活P53-P21通路抑制PASMC的异常增殖和迁移,促进细胞凋亡,为PAH治疗提供了一种潜在的方法。