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

Abstract

The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)–dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.

Endothelial dysfunction and immunothrombosis in sepsis

“…Linagliptin, a dipeptidyl peptidase-4 inhibitor used for diabetes treatment, was also found to ameliorate LPS-induced pulmonary thrombosis in mice via decreased endothelial TF expression. This effect was shown to be mediated through linagliptin-induced activation of the Akt/eNOS pathway and subsequent NO production ( 59 ). Noteworthy, linagliptin or the glucagon-like peptide-1 (GLP-1) analog, liraglutide, were shown to have further inhibitory effects on platelet thrombin generation and platelet aggregation via the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway ( 293 ).…”

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

“…For instance, gliptins exert a notably anti-inflammatory effect. In experimental models of inflammation and fibrosis, gliptins suppress macrophage activation, ameliorate inflammation, reduce cytokine production, mitigate systemic inflammatory response, and reduce microvascular thrombosis [ 148 , 149 , 150 ]. In patients with T2DM and symptomatic coronary artery disease, the addition of vildagliptin to ongoing metformin showed better glycemic control, lower inflammatory markers (IL-1β and C reactive protein), higher protective markers (adiponectin and HDL-C), and improved lipid profile compared to glimepiride/metformin therapy [ 151 ].…”

Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

“…In contrast to AP, the activity of dipeptidyl peptidase-4 (DPP4), confined to the venous part of heart capillaries, was significantly reduced in hairless SHR M , regardless of the sex, but not in wild type SHR when compared to WKY rat hearts. Vascular DPP4 is a transmembrane serine protease that degrades vasoactive peptides and hormones and is also involved in collagen metabolism [ 30 ] and proinflammatory processes [ 31 ], while the inflammation deteriorates the Cx43 channel function [ 32 ]. Lower DPP4 activity attenuated capillary rarefaction and myocardial inflammation and contributed to a favorable metabolism in an ischemic heart [ 33 ].…”