Abstract 294: Inhibiting Myeloperoxidase Restores Collateralization in Ischemic Hindlimbs in Diabetes
Background: Myeloperoxidase (MPO) is released from activated neutrophils and is believed to play a causal role in peripheral vascular disease (PVD). Leptin receptor deficient (db/db) mice are a model of type 2 diabetes mellitus (DM) that are regularly used to investigate mechanisms by which DM impairs endothelial cell (EC) function and increases PVD.
Objectives and Methods: To investigate MPO’s role in ischemic disease in DM, db/db mice were pretreated with N-acetyl-lysyltyrosylcysteine amine (KYC, subQ, 1 mg/kd/d) for 7 days, subjected to hindlimb ischemia, treated with KYC for 14 days and changes in blood flow determined by Laser Doppler. Hindlimbs were examined for changes in neutrophil counts, chlorotyrosine (Cl-Tyr), 4-hydroxynoneal (4-HNE), advanced glycation end-products (AGE) expression via immunohistochemistry and immunoblotting. Hindlimb matrix was used to determine the effects of DM and KYC treatments on matrix-dependent EC proliferation and migration.
Results: Percent change in blood flow in ischemic legs (IL) of C57BL/6J mice increased to ~50% by day 14 post femoral artery ligation compared to day 0. In contrast, blood flow in IL of untreated db/db mice increased to ~13%, ~15% and ~17% on days 3, 7 and 14. Blood flow in IL of db/db mice treated with KYC increased to ~20%, ~43% and ~47% on days 3, 7 and 14. KYC treatments decreased neutrophil counts, Cl-Tyr, 4-HNE and AGE expression in IL. Further, proliferation and migration were increased when EC were cultured on matrix isolated from KYC-treated db/db mice compared to matrix from untreated db/db mice. Interestingly, KYC treatments had no effect on blood glucose in db/db mice.
Conclusions: MPO increases oxidative stress, tissue injury and impairs EC function to increase PVD in db/db mice. KYC inhibition of MPO reduces oxidative stress and tissue injury and restores EC function and blood flow in db/db mice. These data suggest that KYC may be effective for treating PVD in patients with diabetes.
Author Disclosures: D. Weihrauch: None. J.G. Krolikowski: None. D.W. Jones: None. H. Zhang: None. K.A. Pritchard: None.
- © 2015 by American Heart Association, Inc.