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

Abstract

Jiying Liu,1– 3 Guangyao Fang,2,4 Cong Lan,2 Chenming Qiu,5 Li Yao,2 Qian Zhang,2 Jingtang Hu,2 Yaolei Zhang,6 Yongjian Yang,1,2 Yan Zhang1,2 1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Cardiology, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China; 3Department of Cardiology, The Third People’s Hospital of Yibin, Yibin, Sichuan, 644000, People’s Republic of China; 4College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610083, People’s Republic of China; 5Department of Burn and Plastic Surgery, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China; 6Basic Medical Laboratory, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of ChinaCorrespondence: Yongjian Yang, Department of Cardiology, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China, Tel [phone], Email [email protected] Yan Zhang, Department of Cardiology, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China, Tel [phone], Email [email protected]: 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-κB (NF-κB) signaling activation plays a pivotal role in the pathogenesis of PAH. Forsythoside B (FTS•B) possesses inhibitory effect on NF-κB 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 co-treated 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-κB activator PMA was used to investigate the role of NF-κB 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-1β and IL-6 caused by MCT were decreased by FTS•B. Mechanistically, MCT-triggered phosphorylation of p65, IκBα, IKKα and IKKβ 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-κB activation.Conclusion: FTS•B effectively attenuates PAH by suppressing the NF-κB 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-κB signaling pathway, pulmonary vascular remodeling, pulmonary artery smooth muscle cell

Keywords

• forsythoside b
• pulmonary arterial hypertension
• nf-κb signaling pathway
• pulmonary vascular remodeling
• pulmonary artery smooth muscle cell