Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis

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.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model

“…L-NAME treatment began two weeks before LPS injection. Linagliptin treatment (5 mg/kg/day) was administered by oral gavage [ 37 ] for 2 days prior to LPS injection. LPS (10 mg/kg) purified from Salmonella typhosa was administered by single intraperitoneal injection 24 h before the end of the experiment.…”

DMAG, a novel countermeasure for the treatment of thrombocytopenia

“…PRP was counted by Hematology Analyzer to adjust platelet density at 300 × 10 9 per sample. After the stimulation of ADP (Helena Laboratories, USA), platelet aggregation was analyzed with a turbidimetric aggregation-monitoring device (Helena Laboratories, Beaumont, TX, United States) according to previously report (Li et al 2020 ).…”

Glycaemic Control in Patients Undergoing Percutaneous Coronary Intervention: What Is the Role for the Novel Antidiabetic Agents? A Comprehensive Review of Basic Science and Clinical Data

“…DPP-4i have also been demonstrated to increase the mobilization and activity of circulating endothelial progenitor cells (EPCs), which play a crucial role in angiogenesis and endothelial repair [22]. Finally, several clinical and pre-clinical studies indicated the anti-thrombotic effects of DPP-4i mediated by mechanisms such as attenuation of mitochondrial respiration and thrombin-induced aggregation, increased intracellular cyclic AMP levels improving NO availability, inhibitory effects on tyrosine phosphorylation and intracellular free calcium [137,147,148].…”