Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Inhibition of myeloperoxidase increases revascularization and improves blood flow in a diabetic mouse model of hindlimb ischaemia. Diab Vasc Dis Res 2020 Mar-Apr;17(3):1479164120907971

Date

04/01/2020

Pubmed ID

32223319

DOI

10.1177/1479164120907971

Scopus ID

2-s2.0-85082634881

Abstract

OBJECTIVE: Diabetes mellitus is a significant risk factor for peripheral artery disease. Diabetes mellitus induces chronic states of oxidative stress and vascular inflammation that increase neutrophil activation and release of myeloperoxidase. The goal of this study is to determine whether inhibiting myeloperoxidase reduces oxidative stress and neutrophil infiltration, increases vascularization, and improves blood flow in a diabetic murine model of hindlimb ischaemia.

METHODS: Leptin receptor-deficient (db/db) mice were subjected to hindlimb ischaemia. Ischaemic mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC) to inhibit myeloperoxidase. After ligating the femoral artery, effects of treatments were determined with respect to hindlimb blood flow, neutrophil infiltration, oxidative damage, and the capability of hindlimb extracellular matrix to support human endothelial cell proliferation and migration.

RESULTS: KYC treatment improved hindlimb blood flow at 7 and 14 days in db/db mice; decreased the formation of advanced glycation end products, 4-hydroxynonenal, and 3-chlorotyrosine; reduced neutrophil infiltration into the hindlimbs; and improved the ability of hindlimb extracellular matrix from db/db mice to support endothelial cell proliferation and migration.

CONCLUSION: These results demonstrate that inhibiting myeloperoxidase reduces oxidative stress in ischaemic hindlimbs of db/db mice, which improves blood flow and reduces neutrophil infiltration such that hindlimb extracellular matrix from db/db mice supports endothelial cell proliferation and migration.

Author List

Weihrauch D, Martin DP, Jones D, Krolikowski J, Struve J, Naylor S, Pritchard KA Jr

Authors

Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiogenesis Inducing Agents
Animals
Cell Movement
Cell Proliferation
Cells, Cultured
Diabetes Mellitus
Disease Models, Animal
Enzyme Inhibitors
Extracellular Matrix
Hindlimb
Human Umbilical Vein Endothelial Cells
Humans
Ischemia
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal
Neovascularization, Physiologic
Neutrophil Infiltration
Neutrophils
Oligopeptides
Oxidative Stress
Peroxidase
Receptors, Leptin
Regional Blood Flow
Signal Transduction
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a