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Context: Pulmonary hypertension (PH) is a complication of numerous pulmonary conditions. Previous studies have confirmed that Selaginella doederleini has pharmacological effects against many cancers, and triflavones have been newly isolated as one of its active ingredients, with antioxidant and antitumor activities. The chronic hypoxia model is one of the models most used to study PH pathogenesis and treatment.Objective: The present study was designed to investigate the protective effects of triflavones from selaginella doederlleini against PH and on the proliferation and apoptosis of ASMCs in a hypoxia-induced PH model in rats.Methods: The research team performed an animal study.Setting: The study took place at the Tongji Medical College at the Huazhong University of Science and Technology in Wuhan, Hubei, PR China.Animals: The animals were 40 specific pathogen free (SPF), male SD rats weighing 200 ± 20 g each.Intervention: The animals were divided into 4 groups, with 10 animals in each group: (1) the control group, (3) the hypoxia group (PH group), (3) the control + triflavones group (Tri group) and (4) the hypoxia + triflavones group (PH + Tri group). The rats in 2 hypoxia groups were exposed to 10% oxygen to induce PH, and the animals in the 2 control groups were exposed to room air, both for 3 consecutive weeks. Animals in the 2 triflavones groups were injected with 200 μL of triflavones-100 mg/mL dissolved in 0.9% normal saline-and the animals in the control and PH groups were injected with 200 μL of 0.9% normal saline.Outcome Measures: In vitro, the primary aorta smooth muscle cells (ASMCs) were isolated, and the proliferation and apoptosis of the ASMCs were assayed by CCK-8 kit and flow cytometry. The expression levels of the alpha-smooth muscle actin (α-SMA), transforming growth factor beta 1 (TGF-β1), and phosphoinositide 3-kinases (P13K)/ protein kinase B (Akt) in the ASMCs were also assayed by Western blot.Results: Triflavones effectively decreased mPAP, the ratio of RV/ (LV + S), and the thickness of the arteries of the PH + Tri group. Furthermore, triflavones reversed the increased proliferation and inhibited apoptosis induced by chronic hypoxia for that group. Hypoxia increased TGF-β1 protein expression and the activation of P13K/Akt, as shown in the PH group, and was abrogated by the triflavones.Conclusion: Triflavones are promising protective agents against PH due to their inhibitory effects on vascular remodeling through P13K/Akt signaling. [ABSTRACT FROM AUTHOR]