Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression
Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression
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DOI：
10.1253/circj.cj-14-1218
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发表时间：
2015-12-01
影响因子：
3.3
通讯作者：
Takahashi, Naohiko
中科院分区：
文献类型：
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作者：
Saito, Shotaro;Thuc, Luong Cong;Takahashi, Naohiko
背景：葡萄糖波动（GF）对糖尿病（DM）心血管并发症的影响一直备受关注。本研究探讨GF是否会增加心脏缺血再灌注的易感性。方法与结果：将雄性大鼠随机分为对照组、DM组和DM合并GF组。注射链脲佐菌素诱导DM，饥饿和注射胰岛素诱导血糖波动。一个连续方案包括4天内2次低血糖发作。离体心脏缺血20分钟/再灌注30分钟。GF患者的心肌梗死面积大于持续高血糖患者。GF降低了过氧化氢酶和超氧化物歧化酶的活性，上调了NADPH氧化酶和硫氧还蛋白相互作用蛋白的表达，同时增加了活性氧（ROS）。糖尿病心脏线粒体肿胀，嵴破坏；他们被GF进一步摧毁。微阵列分析显示，GF心脏中microRNA -200c和miRNA-141表达丰富。miRNA-200c和miRNA-141过表达降低线粒体超氧化物歧化酶和过氧化氢酶活性，增加ROS水平。同时，miRNA-200c和miRNA-141的敲低可显著降低GF暴露心肌细胞的ROS水平。结论：GF增加了糖尿病心脏ROS的生成，增强了缺血/再灌注损伤。miRNA-200c和miRNA-141的上调可能是ROS增加的原因。
Background: The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated.Methods and Results: Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF.Conclusions: GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.