抑制二肽基肽酶-IV 酶活性可保护大鼠免受心肌缺血-再灌注损伤。
Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats.
作者信息
Chua Sarah, Lee Fan-Yen, Tsai Tzu-Hsien, Sheu Jiunn-Jye, Leu Steve, Sun Cheuk-Kwan, Chen Yung-Lung, Chang Hsueh-Wen, Chai Han-Tan, Liu Chu-Feng, Lu Hung-I, Yip Hon-Kan
出版信息
J Transl Med. 2014 Dec 13;12:357. doi: 10.1186/s12967-014-0357-0.
BACKGROUND
We investigated whether attenuating dipeptidyl peptidase-IV (DPP4) enzyme activity protected rat heart from ischemia-reperfusion (IR) injury (40-min left anterior descending coronary artery ligation followed by 72 h reperfusion).
METHODS AND RESULTS
Adult male Fischer 344 rats (n = 24) were equally divided into sham-control (WT-SC), WT-IR, and WT-IR-Sita (oral sitagliptin 400 mg/kg/day for 3 days) groups, whereas adult male DPP4-deficiency (DPP4(D)) rats (n = 16) were equally divided into DPP4(D)-SC and DPP4(D)-IR groups. Animals were sacrificed at 72 h after reperfusion with collection of heart specimens. Infarct area (H&E), collagen deposition (Sirius-red stain), fibrotic area (Masson's trichrome), and fluorescent-ROS intensity (H2DCFDA-labeling myocardium) of left ventricle were significantly higher in WT-IR than those in other groups, significantly higher in WT-IR-Sita and DPP4(D)-IR groups than in WT-SC and DPP4(D)-SC groups (all p < 0.001), but there was no difference between the latter two groups. Protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NOX-1, NOX-2), inflammation (TNF-α, NF-κB, MMP-9, VCAM-1), apoptosis (mitochondrial Bax, cleaved caspase-3 and PARP), myocardial damage markers (cytosolic cytochrome-C, γ-H2AX), and number of inflammatory cells (CD14+, CD68+, CD40+ cells) showed a pattern identical to that of histological changes among all groups (all p < 0.005), whereas markers of anti-apoptosis (Bcl-2) and mitochondrial integrity (mitochondrial cytochrome-C) as well as left ventricular ejection fraction showed an opposite pattern (all p < 0.001). Protein expressions of anti-oxidants (HO-1, NQO-1), angiogenesis factors (SDF-1α, CXCR4), and glycogen-like-peptide-1-receptor were significantly higher inWT-IR-Sita and DPP4(D)-IR than those in other groups (all p <0.001).
CONCLUSION
Abrogation of DPP4 activity protects against myocardial IR injury and preserved heart function.
背景
我们研究了减弱二肽基肽酶-IV（DPP4）酶活性是否能保护大鼠心脏免受缺血再灌注（IR）损伤（左冠状动脉前降支结扎40分钟，随后再灌注72小时）。
方法与结果
成年雄性Fischer 344大鼠（n = 24）平均分为假手术对照组（WT-SC）、WT-IR组和WT-IR-Sita组（口服西他列汀400 mg/kg/天，共3天），而成年雄性DPP4缺陷（DPP4(D)）大鼠（n = 16）平均分为DPP4(D)-SC组和DPP4(D)-IR组。再灌注72小时后处死动物并收集心脏标本。WT-IR组左心室梗死面积（苏木精-伊红染色）、胶原沉积（天狼星红染色）、纤维化面积（Masson三色染色）和荧光活性氧强度（2',7'-二氯二氢荧光素二乙酸酯标记心肌）显著高于其他组，WT-IR-Sita组和DPP4(D)-IR组显著高于WT-SC组和DPP4(D)-SC组（均p < 0.001），但后两组之间无差异。氧化应激（氧化蛋白）、活性氧（NOX-1、NOX-2）、炎症（TNF-α、NF-κB、MMP-9、VCAM-1）、凋亡（线粒体Bax、裂解的半胱天冬酶-3和PARP）、心肌损伤标志物（胞质细胞色素C、γ-H2AX）的蛋白表达以及炎症细胞数量（CD14+、CD68+、CD40+细胞）在所有组中的变化模式与组织学变化相同（均p < 0.005），而抗凋亡标志物（Bcl-2）和线粒体完整性标志物（线粒体细胞色素C）以及左心室射血分数则呈现相反模式（均p < 0.001）。WT-IR-Sita组和DPP4(D)-IR组中抗氧化剂（HO-1、NQO-1）、血管生成因子（SDF-1α、CXCR4）和胰高血糖素样肽-1受体的蛋白表达显著高于其他组（均p < 0.001）。
结论
消除DPP4活性可预防心肌IR损伤并保留心脏功能。
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