Investigating The Effects Of Pterostilbene On Pressure Over Load-induced Heart Failure:Network Pharmacology And In Vitro/In Vivo Validation

ObjectPathological remodeling has been proven to be a key factor in the progression of chronic heart failure(CHF).However,safe and effective therapeutic agents for CHF are still lacking.The optimum strategy for CHF treatment has yet to be elucidated.Pterostilbene is a biological drug with antioxidant,anti-proliferative and anti-inflammatory effects.Recent studies have reported its protective effect on cardiovascular system.It is still uncertain whether pterostilbene can ameliorate pressure overload-induced CHF and its potential mechanisms.This study aimed to investigate the role of pterostilbene in heart failure and elucidate the underlying mechanisms.MethodsRats were respectively treated with pterostilbene(20mg/kg/d)or vehicle after abdominal aortic coarctation(AAC)or sham surgery for 8 weeks.Myocardial hypertrophy and fibrosis were assessed as well as cardiac functions.In addition,rats’ hearts were harvested for histopathological and molecular analyses including immunofluorescence,Masson’s trichrome staining,HE staining,and Western blot.The cell model of hypertrophy and fibrosis was established by angiotensin Ⅱ(Ang-Ⅱ)and treated with pterostilbene.The network was constructed by heart failure genes and predicted targets reversed by pterostilbene.The targets were confirmed in vivo and verified in vitro by inhibiting signaling pathway specifically.ResultsMyocardial hypertrophy and fibrosis was suppressed in CHF rat model after pterostilbene treatment.But left ventricular ejection fraction wasn’t improved significantly.Subsequently,the results in vitro experiment revealed that Ang-Ⅱinduced cardiomyocyte hypertrophic activity and fibroblast proliferation and transformation of myofibroblast were significantly alleviated after treatment with pterostilbene.Next,86 potential targets from protein-protein interaction(PPI)were used to illustrate the interaction between targets.KEGG pathway analysis indicated that mTOR pathway was enriched.The key targets PIK3 CA,mTOR were selected as molecular docking with pterostilbene from the drug-target network and showed good activity in binding with the targets.In in vitro experiments,the inhibitor of phosphatidylinositol 3 kinase(PI3K)LY294002,could abrogate the anti-hypertrophic effect of pterostilbene,demonstrating that pterostilbene was mediated by upregulating PI3K/AKT/mTOR pathway.ConclusionPterostilbene ameliorates cardiac hypertrophy and fibrosis in pressure overload-induced chronic heart failure by activating PI3K/AKT/mTOR signaling pathway.