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

• Published in: International journal of molecular sciences Vol. 23; no. 6; p. 3065
• Main Authors: Wang, Shen-Chih, Wang, Xiang-Yu, Liu, Chung-Te, Chou, Ruey-Hsing, Chen, Zhen Bouman, Huang, Po-Hsun, Lin, Shing-Jong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.03.2022; MDPI
• Subjects: AKT protein; Animals; Cell adhesion; Cytokines; Diabetes mellitus; Dipeptidyl Peptidase 4; dipeptidyl peptidase-4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Disease Models, Animal; Drugs; Endothelial cells; Endothelium; Experiments; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents - pharmacology; IL-1β; Inflammation; Inflammation - drug therapy; Inflammatory response; Intercellular adhesion molecule 1; Kinases; linagliptin; Linagliptin - pharmacology; Linagliptin - therapeutic use; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lungs; Mice; Microcirculation; Microvasculature; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Pathophysiology; Peptidase; Peptidases; Perfusion; Phosphorylation; Sepsis; Sepsis - complications; Sepsis - drug therapy; Systemic inflammatory response syndrome; Thrombosis; Thrombosis - drug therapy; Thrombosis - etiology; Tissue factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Umbilical vein; dipeptidyl peptidase-4 inhibitor; linagliptin; thrombosis; inflammation; sepsis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23063065

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.