Gut microbial metabolite 4-cresol attenuates myocardial ischemia/reperfusion injury in diabetes
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摘要:
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 ischemia-reperfusion, 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，0.15 µL/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 tyrosine-phosphorylation-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。 Abstract: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, 0.15 µL/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. -
Key words:
- 4-cresol /
- apoptosis /
- oxidative stress /
- diabetic heart /
- myocardial ischemia/reperfusion
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图 1 4-甲酚减少糖尿病状态下缺血/再灌注大鼠的心肌损伤
CON：正常对照组；DM：糖尿病组；1：DM+Sham组；2：DM+MI/R组；3：DM+MI/R+4-cresol组。n=6。与CON相比，bP<0.01；与DM+Sham相比，dP<0.01；与DM+MI/R相比，eP<0.05，fP<0.01
图 2 4-甲酚减少糖尿病状态下缺血/再灌注大鼠的心肌细胞凋亡
1：DM+Sham 组；2：DM+MI/R 组；3：DM+MI/R+4-cresol 组。n=6。与DM+Sham相比，dP<0.01；与DM+MI/R相比，fP<0.01
图 3 4-甲酚抑制糖尿病状态下缺血/再灌注大鼠的心肌氧化应激
1：DM+Sham 组；2：DM+MI/R 组；3：DM+MI/R+4-cresol组。n=6。与DM+Sham相比，dP<0.01；与DM+MI/R相比，eP<0.05，fP<0.01
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