用线粒体靶向抗氧化剂（mito-TEMPO）对线粒体活性氧进行治疗性抑制可减轻糖尿病性心肌病。
Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy.
作者信息
Ni Rui, Cao Ting, Xiong Sidong, Ma Jian, Fan Guo-Chang, Lacefield James C, Lu Yanrong, Le Tissier Sydney, Peng Tianqing
机构信息
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ont., Canada N6A 4G5; Departments of Medicine and Pathology, The University of Western Ontario, London, Ont., Canada N6A 4G5.
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
出版信息
Free Radic Biol Med. 2016 Jan;90:12-23. doi: 10.1016/j.freeradbiomed.2015.11.013. Epub 2015 Nov 11.
AIMS
The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy.
METHODS
The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured.
RESULTS
Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation.
CONCLUSIONS
Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.
目的
线粒体是心脏中活性氧（ROS）的重要来源。线粒体ROS的产生与糖尿病性心肌病的发病机制有关，这表明专门针对线粒体ROS的治疗策略可能对这种疾病有益。我们研究了线粒体靶向抗氧化剂米托坦对糖尿病性心肌病的治疗作用。
方法
在链脲佐菌素诱导的1型糖尿病小鼠模型和2型糖尿病db/db小鼠糖尿病发病后给予线粒体靶向抗氧化剂米托坦。分析心脏不良变化并评估心肌功能。用高糖刺激培养的成年心肌细胞，测量线粒体超氧化物生成和细胞死亡情况。
结果
高糖孵育增加了培养心肌细胞中线粒体超氧化物的生成，米托坦可预防这种情况。与米托坦共同孵育可消除高糖诱导的细胞死亡。1型和2型糖尿病小鼠心脏均诱导了线粒体ROS生成和细胞内氧化应激水平。每天注射米托坦30天可抑制糖尿病心脏中线粒体ROS生成，预防细胞内氧化应激水平，减少细胞凋亡并减轻心肌肥大，从而改善1型和2型糖尿病小鼠的心肌功能。与米托坦孵育或抑制含Nox2的NADPH氧化酶可预防高糖刺激的心肌细胞中的氧化应激水平和细胞死亡。机制研究表明，米托坦的保护作用与ERK1/2磷酸化的下调有关。
结论
米托坦对线粒体ROS的治疗性抑制减少了糖尿病小鼠心脏的不良变化并减轻了心肌功能障碍。因此，线粒体靶向抗氧化剂可能是治疗糖尿病心脏并发症的有效疗法。
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