Forsythoside B Mitigates Monocrotaline-Induced Pulmonary Arterial Hypertension via Blocking the NF-KB Signaling Pathway to Attenuate Vascular Remodeling

Purpose: Pulmonary arterial hypertension (PAH) is a devastating disease with little effective treatment. The proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by the nuclear factor-KB (NF-KB) signaling activation plays a pivotal role in the pathogenesis of PAH. Forsythoside B (FTS center dot B) possesses inhibitory effect on NF-KB signaling pathway. The present study aims to explore the effects and mechanisms of FTS center dot B in PAH. Methods: Sprague-Dawley rats received monocrotaline (MCT) intraperitoneal injection to establish PAH model, and FTS center dot B was cotreated after MCT injection. Right ventricular hypertrophy and pulmonary artery pressure were measured by echocardiography and right heart catheterization, respectively. Histological alterations were detected by H&E staining and immunohistochemistry. FTS center dot B's role in PASMC proliferation and migration were evaluated by CCK-8 and wound healing assay. To investigate the underlying mechanisms, Western blotting, immunofluorescence staining and ELISA were conducted. The NF-KB activator PMA was used to investigate the role of NF-KB in FTS center dot B's protective effects against PAH. Results: FTS center dot B markedly alleviated MCT-induced vascular remodeling and pulmonary artery pressure, and improved right ventricular hypertrophy and survival. FTS center dot B also reversed PDGF-BB-induced PASMC proliferation and migration, decreased PCNA and CyclinD1 expression in vitro. The elevated levels of IL-1 beta and IL-6 caused by MCT were decreased by FTS center dot B. Mechanistically, MCTtriggered phosphorylation of p65, IKB alpha, IKK alpha and IKK beta was blunted by FTS center dot B. FTS center dot B also reversed MCT-induced nuclear translocation of p65. However, all these protective effects were blocked by PMA-mediated NF-KB activation. Conclusion: FTS center dot B effectively attenuates PAH by suppressing the NF-KB signaling pathway to attenuate vascular remodeling. FTS center dot B might be a promising drug candidate with clinical translational potential for the treatment of PAH.