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

• Published in: Drug design, development and therapy development and therapy, 2024-03, Vol.18, p.767
• Main Authors: Liu, Jiying, Fang, Guangyao, Lan, Cong, Qiu, Chenming, Yao, Li, Zhang, Qian, Hu, Jingtang, Zhang, Yaolei, Yang, Yongjian, Zhang, Yan
• Format: Article
• Language: English
• Subjects: Enzyme-linked immunosorbent assay; Heart; Heart enlargement; Platelet-derived growth factor; Pulmonary hypertension
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S444605

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-[kappa]B (NF-[kappa]B) signaling activation plays a pivotal role in the pathogenesis of PAH. Forsythoside B (FTS*B) possesses inhibitory effect on NF-[kappa]B signaling pathway. The present study aims to explore the effects and mechanisms of FTS*B in PAH. Methods: Sprague--Dawley rats received monocrotaline (MCT) intraperitoneal injection to establish PAH model, and FTS*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*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-[kappa]B activator PMA was used to investigate the role of NF-[kappa]B in FTS*B's protective effects against PAH. Results: FTS*B markedly alleviated MCT-induced vascular remodeling and pulmonary artery pressure, and improved right ventricular hypertrophy and survival. FTS*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*B. Mechanistically, MCT-triggered phosphorylation of p65, I[kappa]B[alpha], IKK[alpha] and IKK[beta] was blunted by FTS*B. FTS*B also reversed MCT-induced nuclear translocation of p65. However, all these protective effects were blocked by PMA-mediated NF-[kappa]B activation. Conclusion: FTS*B effectively attenuates PAH by suppressing the NF-[kappa]B signaling pathway to attenuate vascular remodeling. FTS*B might be a promising drug candidate with clinical translational potential for the treatment of PAH. Keywords: Forsythoside B, pulmonary arterial hypertension, NF-[kappa]B signaling pathway, pulmonary vascular remodeling, pulmonary artery smooth muscle cell