A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4
A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4
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二肽基肽酶 4 (DPP-4) 抑制剂利格列汀可独立于 DPP-4 减轻心肌梗死后的心脏功能障碍
DOI：
10.1016/j.jphs.2018.12.004
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发表时间：
2019
影响因子：
3.5
通讯作者：
Izumi Yasukatsu
中科院分区：
文献类型：
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作者：
Yamaguchi Takehiro;Watanabe Ayano;Tanaka Masako;Shiota Masayuki;Osada-Oka Mayuko;Sano Soichi;Yoshiyama Minoru;Miura Katsuyuki;Kitajima Shojiro;Matsunaga Shinji;Tomita Shuhei;Iwao Hiroshi;Izumi Yasukatsu
二肽基肽酶-4（DPP-4）抑制剂不仅能改善糖尿病糖耐量异常，而且具有多效的胰腺外效应，如对心肌缺血再灌注损伤的预处理作用。在此，我们使用DPP-4缺陷大鼠研究了DPP-4抑制剂利格列汀的抗重塑作用，在诱导心肌梗死（MI）后，将DPP-4失活突变的Fischer 344大鼠经口给予DPP-4抑制剂利格列汀（5 mg kg−1·d −1）或溶剂，并饮用水，持续4周。利格列汀不影响血流动力学状态、体重和梗死面积。在超声心动图中，利格列汀倾向于改善左心室（LV）收缩功能，并显著改善LV舒张功能。利格列汀组边缘区域间质纤维化和巨噬细胞浸润显著低于溶剂组。与溶剂组大鼠相比，利格列汀组大鼠边缘区的纤维化相关基因表达（如胶原蛋白I和转化生长因子-β1（TGF-β1））以及炎症相关表达（如巨噬细胞趋化蛋白1和基质金属蛋白酶-2（MMP-2））均受到显著抑制。在DPP-4缺陷的心脏成纤维细胞中，利格列汀可降低TGF-β1和MMP-2的蛋白水平，利格列汀可通过DPP-4非依赖性途径减轻MI诱导的心脏重构。
Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats.After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg−1·day−1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-β1 (TGF-β1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-β1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts.Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.