4-甲酚减轻糖尿病大鼠心肌缺血/再灌注损伤

Gut microbial metabolite 4-cresol attenuates myocardial ischemia/reperfusion injury in diabetes

目的旨在研究4-甲酚对糖尿病(diabetic mellitus,DM)大鼠心肌缺血/再灌注(myocardial ischemiareperfusion,MI/R)损伤的保护作用,并初步探讨其机制。方法取雄性SD大鼠,分为正常对照组和糖尿病组。利用高脂饲料联合链脲霉素诱导2型糖尿病大鼠模型。造模成功后,随即分为3组:糖尿病假手术组(DM+Sham)、糖尿病心肌缺血/再灌注组(DM+MI/R)和糖尿病心肌缺血/再灌注+4-甲酚组(DM+MI/R+4-cresol)。4-cresol组采用植入式胶囊渗透压泵给药(5.5 mmol/L 4-cresol,0.15μL/h),其余给予生理盐水。6周后,采用结扎冠状动脉左前降支30 min再灌注3 h的方法建立心肌缺血/再灌注模型。再灌注结束处死大鼠,检测心肌梗死和细胞凋亡。检测心肌氧化应激程度。测定心肌双底物特异性酪氨酸磷酸化调节激酶1a(dual specificity tyrosinephosphorylation-regulated kinase 1A,Dyrk1A)表达以及细胞凋亡信号调节激酶1(apoptosis signal-regulating kinase,ASK1)磷酸化水平。结果4-甲酚可有效减轻糖尿病大鼠心肌损伤,表现为心肌梗死面积下降、血清肌酸激酶(Ccreatine kinase,CK)及乳酸脱氢酶(Llactic dehydrogenase,LDH)活性降低、心肌细胞凋亡减少(P<0.05,P<0.01),同时4-甲酚显著抑制心肌丙二醛(malonic dialdehyde,MDA)含量(P<0.01),增加超氧化物歧化酶(superoxide Dismutase,SOD)含量、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)含量(P<0.05,P<0.01),表明4-甲酚可以有效减轻氧化应激。此外,4-甲酚处理后,心肌Dyrk1A表达以及ASK1的磷酸化水平显著降低(P<0.05)。结论4-甲酚可显著减轻糖尿病大鼠心肌缺血/再灌注损伤,其具体机制与激活Dyrk1A信号,抑制氧化应激,减轻细胞凋亡相关。

AIM To observe the protective effect of 4-cresol on diabetic hearts following ischemia/reperfusion(I/R)and to explore the possible molecular mechanisms.METHODS Forty-six male SD rats were randomly divided into normal control(CON)group and diabetes mellitus(DM)group.The DM rat model was induced by high-fat diet combined with a low-dose intraperitoneal injection of streptozotocin.Diabetic rats were randomly subdivided into three groups:Sham-operated DM rats(DM+Sham),DM+MI/R,and DM+MI/R+4-cresol(5.5 mmol/L 4-cresol,0.15μL/h).The MI/R model was established by coronary artery ligation.After 30 min of ischemia,the myocardium was reperfused for 3 h.RESULTS 4-cresol significantly attenuated myocardial injury in diabetes as evidenced by decreased infarct size,serum CK and LDH activities and cell apoptosis.Moreover,4-cresol increased superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)and decreased malonaldehyde(MDA)in I/R hearts(P<0.05,P<0.01).Additionally,4-cresol supplementation markedly inhibited dual specificity tyrosine-phosphorylation-regulated kinase 1A(Dyrk1A)expression and decreased the phosphorylation of apoptosis signal-regulating kinase 1(ASK1)(P<0.05,P<0.01).CONCLUSION 4-cresol effectively inhibits Dyrk1A expression,reduces oxidative stress and cardiomyocyte apoptosis and eventually alleviates MI/R injury in diabetic hearts.