| Backgrounds:Vascular remodeling is a prominent feature and pathological basis of hypertension and many cardiovascular diseases,which is increasingly regarded as a big risk marker of cardiovascular diseases.It is important to effectively prevent or turnover vascular remodeling in hypertension,as a potential and critical method in preventing or ameliorating hypertension.Although a variety of antihypertensive agents have been used in clinical,the targeted agent for vascular remodeling is comparatively lacked,and the agents cannot effectively remove pathogenic factors or reverse the remodeling process.Therefore,research or discovery of a new and safe agent antagonizing vascular remodeling is becoming increasingly important and urgent.Traditional Chineses medicine has an important role in the treatment of cardiovascular diseases.Frankincense(Boswellia Species)excerts protection in multiple cardiovascular diseases,inhibits vascular fibrosis and remodeling,as reported before.Acetyl-11-keto-?-boswellic acid(AKBA)is a pentacyclic triterpene compound from plant Boswellia serrate gum resins,and one of the most potent active principles.B.serrate extract has shown anti-inflammatory and antioxidant effect for clinical use with good tolerability.And it also has good anti-fibrotic effect through TGF-? and MMPs,and inhibits tissue fibrosis and remodeling.For example,studies have revealed that boswellic acids markedly decreases transforming growth factor-?1(TGF-?1)and TGF-?1-induced pulmonary artery fibrosis,and notably prevents colonic fibrosis through TGF-?1/Smad3 pathway.Moreover,AKBA could effectively modulate inflammatory responses involved NF-?B,reduce MMPs secretion,decrease vascular intima damage,and thus exert vasoprotection.Transforming growth factor-?1(TGF-?1)and matrix metalloproteinases(MMPs)are recognized as key factors in vascular remodeling.Abnormal activation of TGF-?1 contributes to extracellular matrix accumulation,collagen deposition and MMPs activation as a result of cell migration and vascular tissue rearrangement.Recently,abundant evidence shows that endogenous ROS and inflammation stimulate release and activation of TGF-?1 and MMPs which initiate from vascular adventitial fibroblast and could be antagonized by drugs with antioxidant and anti-inflammation effects,so as to exert potent vasoprotection.Thereby,safe and non-toxic natural compounds owing antioxidant or anti-inflammation effects will be a good choice for vasoprotection and anti-remodeling.Accordingly,we hypothesize that AKBA may also be beneficial for vascular remodeling in hypertension by blocking fibrotic TGF-?1 and MMPs factors associated with inflammation and ROS,which have little been investigated in vascular wall of hypertension.Purpose:1.To explore the vasoprotection of AKBA on vascular remodeling in hypertension.2.To explain the potential mechanisms of AKBA on vasoprotection.Methods: In present study,the pharmacological effects of AKBA on vascular remodeling of hypertension and the potential mechanisms are explored in SHR and fibroblast respectively.a)In vivo experiment,spontaneously hypertensive rats(SHR,male,6w)were treated with AKBA(20,40 mg/kg)by gavage for 8 weeks,to preliminarily evaluate pharmacological effect of AKBA.1.Blood pressure was detected by tail-cuff method.2.Hemorheology was evaluated by whole blood viscosity.3.Biochemical detection was used for vasoactive substances.4.H&E staining was used to assess morphological alterations of vascular walls.5.Masson staining was used to assess collagen deposition.6.Immunofluorescence and immunohistochemistry were used to detect TGF-?1/Smad3 and MMP2 expression on vascular walls.b)In vitro experiment,fibroblast was pretreated with AKBA(1,2,4 ?M)1h before Ang II(0.1 ?M)stimuli for 24 h.1.ELISA was used to detect inflammatory factors and TGF-?1 secretion.2.Intracellular ROS production was assessed by Flow cytometer.3.Fibroblast viability was evaluated by MTT assay.4.Fibroblast migration was evaluated by Transwell assay.5.Western blot was used to assess the effect of AKBA on TGF-?1/Smad3 pathway and MMP2/9 activation.Protein levels of TGF?-1/Smad3,P-Smad3,Smad7,MMP2/9 in cell extract were detected.Results: The data shows that AKBA exerts good anti-inflammation and antioxidant effects in vivo and vitro,and effectively decreases fibrotic factors TGF-?1 and MMPs activation,and thus improves vascular remodeling.1.The animal experiments indicate that at early stage of hypertension,SHR has been challenged with chronic vasoconstriction,inflammation and severe oxidative stress along with marked vascular remodeling.Compared with WKY,vascular cross-sectional area,vascular thickness and media/lumen ratio of SHR are significantly increased(P<0.05).AKBA markedly attenuates oxidative stress and inflammatory responses,and balances vasoconstrictor and vasodilator levels,independently of blood pressure and whole blood viscosity.Importantly,AKBA effectively decreases vascular remodeling by restoring vascular morphological features,decreasing collagen deposition in vascular wall.Moreover,AKBA markedly reduces TGF-?1/Smad3 and MMP2 expression as shown in immunofluorescence and immunohistochemistry.2.In cultured fibroblast,AKBA dose-dependently decreases ROS production and inflammatory factors,and decreases viability and migration of fibroblast induced by Ang II stimuli.Results of western blot demonstrates that AKBA significantly decreases TGF-?1/Smad3 and MMPs,and decreased P-Smad3/Smad3,Smad7 and MMP2/9 levels in cell extracts.Conclusion:1.AKBA shows good pharmacological effects on vascular remodeling of hypertension,decreases vascular remodeling associated with the good anti-inflammation and antioxidant effects.2.AKBA is able to inhibit TGF-?1 and MMPs activation,and thus prevents fibrotic process on vascular walls and exerts vasoprotection.3.AKBA can be an alternative therapeutic agent for vascular remodeling in hypertension,which provides new idea and theoretical support for the prevention and treatment of hypertension. |
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