Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis.
Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis.
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DOI：
10.3389/fphar.2020.585612
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发表时间：
2020
影响因子：
5.6
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Li Y;Li R;Feng Z;Wan Q;Wu J
背景资料：二肽基肽酶-4（DPP-4）的药理学抑制可增强肠促胰岛素的作用，DPP-4是治疗2型糖尿病和降低心血管风险的药物靶点。然而，关于DPP-4可能导致缺血性心血管事件的非肠内分泌途径知之甚少。 研究方法：我们检验了抑制DPP-4可通过防止血小板线粒体功能障碍和释放来抑制血小板活化和动脉血栓形成的假设。在小鼠中研究了DPP-4药理学抑制对颈动脉血栓形成、血小板聚集和血小板线粒体呼吸信号通路的影响。 结果如下：与溶媒给药小鼠相比，高剂量利格列汀（一种强效DPP-4抑制剂）给药并饲喂正常饲料的小鼠的血小板依赖性动脉血栓形成显著延迟。凝血酶诱导DPP-4表达和活性，利格列汀预处理的血小板显示凝血酶诱导的聚集减少。当凝血酶刺激血小板时，利格列汀阻断磷酸二酯酶活性并抑制环AMP减少。利格列汀可增强一氧化氮对血小板聚集的抑制作用。生物能量学特征显示，经利格列汀预处理的血小板对凝血酶的反应显示耗氧率降低。在透射电子显微镜检查中，利格列汀预处理的血小板显示凝血酶活化血小板的形态学变化明显逆转，包括分泌α颗粒和线粒体减少。 结论：总的来说，这些发现确定了DPP-4在血小板功能和动脉血栓形成中的不同作用。
Background: The pharmacological inhibition of dipeptidyl peptidase-4 (DPP-4) potentiates incretin action, and DPP-4 is a drug target for type 2 diabetes and reducing cardiovascular risk. However, little is known about the non-enteroendocrine pathways by which DPP-4 might contribute to ischaemic cardiovascular events. Methods: We tested the hypothesis that inhibition of DPP-4 can inhibit platelet activation and arterial thrombosis by preventing platelet mitochondrial dysfunction and release. The effects of pharmacological DPP-4 inhibition on carotid artery thrombosis, platelet aggregation, and platelet mitochondrial respiration signaling pathways were studied in mice. Results: Platelet-dependent arterial thrombosis was significantly delayed in mice treated with high dose of linagliptin, a potent DPP-4 inhibitor, and fed normal chow diet compared to vehicle-treated mice. Thrombin induced DPP-4 expression and activity, and platelets pretreated with linagliptin exhibited reduced thrombin-induced aggregation. Linagliptin blocked phosphodiesterase activity and contrained cyclic AMP reduction when thrombin stimulates platelets. Linagliptin increases the inhibition of platelet aggregation by nitric oxide. The bioenergetics profile revealed that platelets pretreated with linagliptin exhibited decreased oxygen consumption rates in response to thrombin. In transmission electron microscopy, platelets pretreated with linagliptin showed markedly reversed morphological changes in thrombin-activated platelets, including the secretion of α-granules and fewer mitochondria. Conclusion: Collectively, these findings identify distinct roles for DPP-4 in platelet function and arterial thrombosis.
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影响因子：
4.8
作者：
Hansen, L;Deacon, CF;Holst, JJ
通讯作者：
Holst, JJ
影响因子：
4.1
作者：
HOLMSEN, H;KAPLAN, KL;DANGELMAIER, CA
通讯作者：
DANGELMAIER, CA
影响因子：
16.6
作者：
Ehinger JK;Piel S;Ford R;Karlsson M;Sjövall F;Frostner EÅ;Morota S;Taylor RW;Turnbull DM;Cornell C;Moss SJ;Metzsch C;Hansson MJ;Fliri H;Elmér E
通讯作者：
Elmér E
影响因子：
6.7
作者：
Cimmino, Giovanni;Tarallo, Roberta;Golino, Paolo
通讯作者：
Golino, Paolo
影响因子：
7.7
作者：
Cameron-Vendrig, Alison;Reheman, Adili;Husain, Mansoor
通讯作者：
Husain, Mansoor