Abstract
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.
Highlights
Platelet-dependent arterial thrombosis was significantly delayed in mice treated with high dose of linagliptin, a potent dipeptidyl peptidase4 (DPP-4) inhibitor, and fed normal chow diet compared to vehicle-treated mice
Platelets pretreated with linagliptin showed markedly reversed morphological changes in thrombin-activated platelets, including the secretion of α-granules and fewer mitochondria
Glucagon-like peptide-1 (GLP-1) is an incretin hormone, and endogenous GLP-1 is rapidly inactivated by dipeptidyl peptidase4 (DPP-4)
Summary
Glucagon-like peptide-1 (GLP-1) is an incretin hormone, and endogenous GLP-1 is rapidly inactivated by dipeptidyl peptidase (DPP-4). The inhibition of DPP-4 with DPP-4 inhibitors is used to improve anti-hyperglycaemic therapy in type 2 diabetes. Increasing evidence indicates the anti-thrombotic effects of GLP-1 receptor agonists and DPP-4 inhibitors. These anti-thrombotic effects were recently confirmed in a model of experimental LPS-induced microvascular thrombus formation in lungs (Steven et al 2017). The loss of DPP-4 activity in endothelial cells upon ischaemia induces a pro-thrombotic status in the endothelium through enhanced tissue factor expression and platelet adhesion (Krijnen et al, 2012). 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. Little is known about the non-enteroendocrine pathways by which DPP-4 might contribute to ischaemic cardiovascular events
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