| A large number of studies have confirmed that both atrial fibrillation(AF)and diabetes mellitus(DM)are usually associated with enhanced inflammatory response.Inflammasome is a kind of activated complex of caspase.The activity of “nucleotidebinding oligomerization domain-like receptor protein 3”(NLRP3)-inflammasome can recognize endogenous risk signals,activate caspase-1,and then activate IL-1β and IL-18,which are involved in the non-infectious inflammatory response of many chronic diseases like coronary heart disease,hypertension and DM.The upstream regulation of NLRP3-inflammasome/Caspase-1/Galectin-3(Gal-3)pathway and the potential benefits of NLRP3-inflammasome inhibitor glibenclamide(GLB)on atrial remodeling or even AF in DM state are still unknown.Aims: The potential upstream mechanism of NLRP3 inflammasome/ Caspase-1/Gal-3 signaling pathway involved in DM atrial remodeling and the effect of NLRP3 inflammasome inhibitor GLB on atrial remodeling were investigated by establishing a rabbit model.Methods: Forty-eight rabbits were randomly averaged into control group(Ctl,n=16),alloxan induced diabetic group(DM,n=16)and GLB-treated diabetic group(DM-G,n=16).The diabetic animal model was established with alloxan,and the three groups of animals were fed under the same conditions for 6 weeks.Among these groups,GLB was taken orally for 6 weeks by rabbits in the DM-G group at a daily dose of 2 mg/kg.The body weight and blood glucose were measured weekly with death situation recorded.After six weeks,eight rabbits from each group were taken follow the principle of randomization for each kind of experiment,the details are as follows.(1)Echocardiography was used for measurements of left atrial anteroposterior diameter(LAD),interventricular septum thickness(IVST),left ventricular end-diastolic dimensions(LVEDD),and left ventricular end-systolic dimensions(LVESD)on the long axis of the left ventricle,while Left ventricular ejection fraction(LVEF)and left atrial ejection fraction(LAEF)were measured by M-mode ultrasound.(2)Aortic systolic and diastolic blood pressure(SBP/DBP),left ventricular end-diastolic pressure(LVEDP)and the maximum rise and fall rate of left ventricular pressure(±dp/dt Max)were measured by hemodynamic test.(3)The vulnerability to AF,atrioventricular Wenckebach cycle length(AVWCL),interatrial conduction time(IACT),atrial effective refractory period(AERP),epicardial conduction velocity and inhomogeneity,AERP dispersion(AERPD)were detected through isolated rabbit hearts that Langendorff perfused.(4)Atrial interstitial fibrosis was assessed by Masson trichrome staining.(5)Serum interleukin(IL)-1β,IL-18 levels and left atrial tissue Caspase-1 activities were examined.(6)The inflammasome and fibrosis-related protein expression of NLRP3,Gal-3,TGF-β1 as well as electrical remodeling related protein of Ca V1.2 were measured by western blot analysis.Results:(1)Compared with controls,the heart weight radio(P<0.01)and atrium weight radio(P<0.01)of diabetic rabbits increased notably.LAD(P<0.01),IVST(P<0.05),PWLV(P<0.01),E/e(P<0.05)were significantly increased in the DM group,while LAD(P<0.01)and PWLV(P<0.05)were decreased by treatment with GLB.There was no significant difference in other cardiac ultrasound parameters between the two groups(P>0.05).(2)Comparison of three groups of animals between two groups shown that there was no significant difference in hemodynamic parameters such as SBP,DBP,LVEDP and ±dp/dt Max(P>0.05).(3)Higher AF inducibility(23/480 vs.5/480,P<0.01)and conduction inhomogeneity index(P<0.01),and slower epicardial conduction velocity(P<0.01)were observed in DM group as against the Ctl group,and when compared with DM group,the AF inducibility(6/480 vs.23/480,P<0.05)and epicardial conduction inhomogeneity index(P<0.01)were decreased in DM-G group,with epicardial conduction velocity becoming faster(P<0.01).(4)Compared with the Ctl group,the infiltration of the inflammatory cells and the interstitial fibrosis was obvious(P<0.01).While compared with DM group,the infiltration of inflammatory cells and the interstitial fibrosis was alleviated in DM-G group(P<0.01).(5)Atrial Caspase-1 activity as well as serum IL-1β,IL-18 levels elevated in diabetic animals as against the Ctl group(P<0.05),while caspase-1 activity and serum IL-18 were suppressed by GLB(P<0.01).(6)GLB decreased the DM-induced protein expression enhancement of NLRP3,Gal-3,TGF-β1 and Ca V1.2 according to western blot analysis(P<0.05).Conclusion: NLRP3-inflammasome/Caspase-1/Gal-3 signaling pathway is related to the pathogenesis of AF in diabetic state.NLRP3-inflammasome inhibitor GLB prevents AF inducibility and moderates atrial electrical and structural remodeling in DM. |
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