金樱子通过调控Src-AKT1轴抑制肺动脉高压平滑肌增殖

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Abstract：ObjectiveToinvestigatethesynergisticmechanismof thetraditional ChinesemedicineRosalaevigataMichx （RLM）for treatmentof pulmonaryarterial hypertension （PAH）.Methods Network pharmacologicalanalysis wascarriedout toscreentheactiveingredientsofRLMandPAHdiseasetargetsandconstructthe"component-target-disease"interaction network，followedbygeneenrichmentanalysisandmoleculardockingstudies.Ithecellexperiments，primaryculturesofat pulmonary arterial smooth muscle cells were exposed to hypoxia for 24h and treated with solventor100，200 and 300mg/mL RLM，and thechanges incellproliferation were detectedusing Western bloting forPCNAand immunofluorescence staining. Intheanimal experiment，maleSDats wererandomizedinto5controlgroup，monocrotaline（MCT）solvent group，andMCT with RLM （100，200 and 300mg/mL ）treatment groups. HE staining and immunofluorescence staining were used to observe histopathological changes in the pulmonary blood vesselsof therats.ResultsSevencoreactive ingredients （including β -sitosterol and kaempferol） in RLM and 39key disease targets were identified，and molecular docking showed that SRC wasa high-affinitytarget.KEGGenrichmentanalysisshowedthatthediferentialgenesweresignificantlyenrichedincalcium signaling andPI3K-AKTpathways.Inrat pulmonaryarterialsmooth muscle cels，hypoxicexposuresignificantlyup-regulated celularexpressonofPCNAandphosphorylationlevelsofSrcandAKT1，whichwereobviouslyloweredbyRLMtreatment. In RLM-treated rat models，the mean pulmonaryartery pressreand right ventricularhypertrophy index （Fulton index）were significantlyreduced，thetricuspidannularplanesystolicexcursion （TAPSE）wasimproved，andpulmonaryvascularwal thickeningand fibrosiswereobviouslyameliorated.ConclusionRLMinhibitspulmonaryarterial smooth musclecell proliferationinratmodelsof hypertensionpossiblybyregulating theSrc-AKTaxis，suggesting thepotentialofRLMasa new natural drug for treatment of pulmonary hypertension.

Keywords： pulmonary hypertension; smooth muscle cell proliferation; AKT1; Src; network pharmacolog

肺动脉高压（PAH）是一种危及生命的疾病，病情进展最终会导致右心衰竭和死亡[1]。（剩余25027字）