Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats.
Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats.
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DOI：
10.1186/s12933-015-0264-6
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发表时间：
2015-08-11
影响因子：
9.3
通讯作者：
Miura T
中科院分区：
文献类型：
--
作者：
Murase H;Kuno A;Miki T;Tanno M;Yano T;Kouzu H;Ishikawa S;Tobisawa T;Ogasawara M;Nishizawa K;Miura T
2型糖尿病（T2 DM）是心肌梗死（MI）后的预后不良因素。在这里，我们假设抑制二肽基肽酶-4（DPP-4）通过改变心脏非梗死区的自噬来改善T2 DM患者MI后的生存率。在基线条件下，OLETF（T2 DM大鼠模型）和LETO（非糖尿病对照）中心肌自噬标志物蛋白水平无显著差异。然而，与LETO中的反应相反，OLETF中心肌梗死后，心肌非梗死区域中的LC 3-II蛋白和LC 3阳性自噬体并未增加。OLETF中改变的自噬反应与MI后AMPK/ULK-1活化的缺乏、Akt/mTOR/S6信号转导的减弱反应和Beclin-1-Bcl-2相互作用的增加相关。维格列汀（10 mg/kg/天皮下注射）治疗，DPP-4抑制剂抑制Beclin-1-Bcl-2相互作用，增加OLETF非梗死区LC 3-II蛋白水平和自噬体，但不能使AMPK/ULK-1或mTOR/S6信号正常化。在本研究中使用的剂量下，血浆胰岛素水平而不是葡萄糖水平显著降低。尽管梗死面积相似，但OLETF组MI后48 h的存活率显著低于LETO组（32 vs. 82%）。维格列汀将OLETF的存活率提高至80%，但其益处被自噬抑制剂氯喹消除。结果表明，维达鲁肽可能通过减弱Bcl-2-Beclin-1相互作用恢复自噬反应来降低T2 DM诱导的MI后急性死亡率增加。本文的在线版本（doi：10.1186/s12933-015-0264-6）包含补充材料，可供授权用户使用。
Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart. Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1–Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1–Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor. The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction. The online version of this article (doi:10.1186/s12933-015-0264-6) contains supplementary material, which is available to authorized users.