Pulmonary hypertension(PH)is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance.One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli.Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis.Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need.Puerarin is an isoflavone compound extracted from the root of Kudzu vine,which is widely used in the treatment of cardiovascular diseases.In the present study,we evaluated the efficacy of puerarin in the treatment of experimental PH.PH was induced in rats by a single injection of MCT(50 mg/kg,sc),and in mice by exposure to hypoxia(10％O2)for 14 days.After MCT injection the rats were administered puerarin(10,30,100 mg·kg-1·d-1,i.g.)for 28 days,whereas hypoxia-treated mice were pre-administered puerarin(60 mg·kg-1·d-1,i.g.)for 7 days.We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models,evidenced by significantly reduced right ventricular systolic pressure(RVSP)and lung injury,improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function,inhibited inflammatory responses in lung tissues,improved resistance to apoptosis and abnormal proliferation in lung tissues,attenuated right ventricular injury and remodeling,and maintained normal function of the right ventricle.We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARy/PI3K/Akt signaling in the lung tissues and right ventricles,which were restored by puerarin administration.In addition,we showed that a novel crystal type Ⅴ(Puer-Ⅴ)exerted better therapeutic effects than the crude form of puerarin(Puer).Furthermore,Puer-V was more efficient than bosentan(a positive control drug)in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles.In conclusion,this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.

Di Chen;Hui-fang Zhang;Tian-yi Yuan;Shu-chan Sun;Ran-ran Wang;Shou-bao Wang;Lian-hua Fang;Yang Lyu;Guan-hua Du

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Key Laboratory of Drug Targets Identification and Drug Screening,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Key Laboratory of Polymorphic Drugs,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

中国药理学报（英文版）

[1]Di Chen;Hui-fang Zhang;Tian-yi Yuan;Shu-chan Sun;Ran-ran Wang;Shou-bao Wang;Lian-hua Fang;Yang Lyu;Guan-hua Du-.Puerarin-V prevents the progression of hypoxia-and monocrotaline-induced pulmonary hypertension in rodent models)[J].中国药理学报（英文版）,2022(09):2325-2339

Kudzu,Puer,bosentan

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