RESUMO
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.
Assuntos
Apoptose , Proliferação de Células , Desoxiadenosinas , Hipertensão Arterial Pulmonar , Animais , Desoxiadenosinas/farmacologia , Desoxiadenosinas/uso terapêutico , Ratos , Masculino , Apoptose/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Proliferação de Células/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Metabolômica , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Monocrotalina , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Remodelação Vascular/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Ácido Linoleico/farmacologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/metabolismo , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. METHODS: The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline(MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used respectively. RESULTS: Through Network Pharmacology and molecular docking , the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. CONCLUSION: This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.