肥大细胞激活促进酒精性心肌病的心肌重构OA

[Objective]To investigate the role and related mechanisms of mast cells(MCs)in alcoholic cardiomyopathy(ACM).[Methods]An ACM model was established in C57BL/6 mice by feeding them with alcohol liquid diet,and some model mice were intervened with cromolyn sodium,a mast cell stabilizer.Cardiac function,myocardial remodeling and the expression of related proteins were evaluated by echocardiography,tissue staining and Western blot.In vitro,neonatal rat ventricular cardiomyocytes(NRVCs)were stimulated with mast cell granules(MCGs)and/or alcohol,and pathway inhibitors were used to explore the underlying mechanisms.[Results]Long-term alcohol feeding caused significant cardiac dysfunction and mast cells activation in mice,accompanied by increased expressions of chymase,NOX2,NOX4 and apoptosis-related protein cleaved Caspase-3(c-Caspase3)in myocardial tissues(P＜0.05).Pretreatment with cromolyn sodium improved cardiac function,inhibited mast cell activation,and reduced the expressions of the above proteins.In vitro experiments showed that treatment with MCGs or alcohol alone up-regulated the expressions of c-Caspase3,NOX2,NOX4 and phosphorylated PKCβ1(p-PKCβ1)in cardiomyocytes,and the combined stimulation of the two had a synergistic effect.Protease-activated receptor 2(PAR2)inhibitor down-regulated the MCG-induced expressions of the above proteins.PKCβ1 inhibitor also inhibited the MCG-induced expressions of c-Caspase3,NOX2 and NOX4.Chymase inhibitor exerted a partial inhibitory effect on MCG-induced cardiomyocyte apoptosis.[Conclusion]During the development of ACM,mast cells are activated,and the released MCGs may promote cardiomyocyte apoptosis through the PAR2-PKCβ1-NOX2/NOX4 signaling pathway,in which chymase plays an important role.