Exploring the mechanism of action of tolvaptan in the treatment of cor pulmonale pulmonary hypertension using network pharmacology and animal-based experiments

Cor pulmonale is a heart disease caused primarily by pulmonary hypertension (PH) due to vascular lesions of the broncho-pulmonary tissue or pulmonary arteries. PH is a central link and prerequisite in the pathogenesis of cor pulmonale. Tolvaptan (TLV) is a drug commonly used in clinical practice to treat patients with cor pulmonale. The aim of our study was to validate the targets and molecular mechanism of TLV in the treatment of cor pulmonale. Network pharmacology was applied to analyze target genes for TLV treatment of PH. Next, the PPI network was utilized to screen the core target. Then, molecular docking was used to detect the binding activity between TLV and Mapk14. Subsequently, the hypoxia-induced PH models were established. The effects of TLV treatment given after Hx induction on lung function and myocardial tissue were analyzed separately. And the Mapk14 expression level was detected by western blot. Finally, the HE staining and TUNEL assay were carried out to examine the lesions and apoptosis in lung and heart tissue, respectively. Network pharmacology showed that there were 34 genes related to TLV and cor pulmonale. A core target was screened according to the PPI network. KEGG analysis revealed the major signaling pathways, including the MAPK and PI3K/Akt signaling pathway. The GO analysis showed the four entries that target genes involved in biological processes, cellular components and molecular functions. Additionally, molecular docking indicated that TLV had binding activity to Mapk14. In vivo experiments demonstrated that TLV ameliorated hypoxia-induced impairment of lung and heart function. The TUNEL assay suggested that TLV effectively improved apoptosis in lung and heart tissue caused by Hx. TLV-targeted Mapk14 treated PH caused by cor pulmonale and effectively mitigated cardiopulmonary impairment caused by Hx.