TY - JOUR

T1 - Selenium-containing indolyl compounds

T2 - Kinetics of reaction with inflammation-associated oxidants and protective effect against oxidation of extracellular matrix proteins

AU - Casaril, Angela M

AU - Ignasiak, Marta T

AU - Chuang, Christine Y

AU - Vieira, Beatriz

AU - Padilha, Nathalia B

AU - Carroll, Luke

AU - Lenardão, Eder J

AU - Savegnago, Lucielli

AU - Davies, Michael J

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - Activated white blood cells generate multiple oxidants in response to invading pathogens. Thus, hypochlorous acid (HOCl) is generated via the reaction of myeloperoxidase (from neutrophils and monocytes) with hydrogen peroxide, and peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent is formed from superoxide radicals and nitric oxide, generated by stimulated macrophages. Excessive or misplaced production of these oxidants has been linked to multiple human pathologies, including cardiovascular disease. Atherosclerosis is characterized by chronic inflammation and the presence of oxidized materials, including extracellular matrix (ECM) proteins, within the artery wall. Here we investigated the potential of selenium-containing indoles to afford protection against these oxidants, by determining rate constants (k) for their reaction, and quantifying the extent of damage on isolated ECM proteins and ECM generated by human coronary artery endothelial cells (HCAECs). The novel selenocompounds examined react with HOCl with k 0.2-1.0 × 108M-1s-1, and ONOOH with k 4.5-8.6 - × 105M-1s-1. Reaction with H2O2 is considerably slower (k < 0.25M-1s-1). The selenocompound 2-phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine provided protection to human serum albumin (HSA) against HOCl-mediated damage (as assessed by SDS-PAGE) and damage to isolated matrix proteins induced by ONOOH, with a concomitant decrease in the levels of the biomarker 3-nitrotyrosine. Structural damage and generation of 3-nitroTyr on HCAEC-ECM were also reduced. These data demonstrate that the novel selenium-containing compounds show high reactivity with oxidants and may modulate oxidative and nitrosative damage at sites of inflammation, contributing to a reduction in tissue dysfunction and atherogenesis.

AB - Activated white blood cells generate multiple oxidants in response to invading pathogens. Thus, hypochlorous acid (HOCl) is generated via the reaction of myeloperoxidase (from neutrophils and monocytes) with hydrogen peroxide, and peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent is formed from superoxide radicals and nitric oxide, generated by stimulated macrophages. Excessive or misplaced production of these oxidants has been linked to multiple human pathologies, including cardiovascular disease. Atherosclerosis is characterized by chronic inflammation and the presence of oxidized materials, including extracellular matrix (ECM) proteins, within the artery wall. Here we investigated the potential of selenium-containing indoles to afford protection against these oxidants, by determining rate constants (k) for their reaction, and quantifying the extent of damage on isolated ECM proteins and ECM generated by human coronary artery endothelial cells (HCAECs). The novel selenocompounds examined react with HOCl with k 0.2-1.0 × 108M-1s-1, and ONOOH with k 4.5-8.6 - × 105M-1s-1. Reaction with H2O2 is considerably slower (k < 0.25M-1s-1). The selenocompound 2-phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine provided protection to human serum albumin (HSA) against HOCl-mediated damage (as assessed by SDS-PAGE) and damage to isolated matrix proteins induced by ONOOH, with a concomitant decrease in the levels of the biomarker 3-nitrotyrosine. Structural damage and generation of 3-nitroTyr on HCAEC-ECM were also reduced. These data demonstrate that the novel selenium-containing compounds show high reactivity with oxidants and may modulate oxidative and nitrosative damage at sites of inflammation, contributing to a reduction in tissue dysfunction and atherogenesis.

U2 - 10.1016/j.freeradbiomed.2017.10.344

DO - 10.1016/j.freeradbiomed.2017.10.344

M3 - Journal article

C2 - 29055824

VL - 113

SP - 395

EP - 405

JO - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

ER -