Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.
Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.
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DOI：
10.14814/phy2.13741
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发表时间：
2018-06
影响因子：
2.5
通讯作者：
Miura T
中科院分区：
文献类型：
--
作者：
Mizuno M;Kuno A;Yano T;Miki T;Oshima H;Sato T;Nakata K;Kimura Y;Tanno M;Miura T
为了探讨SGLT2抑制剂保护糖尿病心脏免受心力衰竭的机制，我们观察了Empa对心肌梗死(MI)后糖尿病心脏非梗死区心肌细胞超微结构的影响。OLETF是一种2型糖尿病的大鼠模型，其非糖尿病对照LETO在组织采样前12小时接受了假手术或左冠状动脉结扎。组织取自后脑室(即心肌梗死大鼠的远端非梗死区)。与LETO相比，OLETF的线粒体数量较多，线粒体较小。FIS1在OLETF中的表达水平高于LETO，而磷酸化Ser637-DRp1、总DRp1、Mfn1/2和OPA1的表达水平与LETO相似。MI通过增加OLETF中Drp1-Ser616的磷酸化来进一步缩小线粒体的大小。LETO组心肌梗死后自噬空泡数量无明显变化，而OLETF组自噬空泡数量减少。OLETF组心肌细胞和组织甘油三酯脂滴增多。给予Empa(每天10 mg/kg)可降低OLETF大鼠的血糖和甘油三酯，并反常增加心肌细胞中的脂滴。Empa抑制OLETF心肌梗死后Fis1表达，增加Bnip3的表达，阻止线粒体大小和自噬空泡数量的减少。结合我们平行研究的结果显示Empa上调了SOD2和过氧化氢酶，结果表明Empa使糖尿病心脏线粒体的大小和数量正常化，并且Empa通过抑制ROS和恢复自噬来防止糖尿病引起的MI后线粒体大小的过度缩小。
To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.