Neutrophil-mediated accumulation of 2-ClHDA during myocardial infarction: 2-ClHDA-mediated myocardial injury

Abstract

The pathophysiological sequelae of myocardial infarction include neutrophil infiltration into the infarct zone that contributes to additional damage to viable tissue and removal of cellular debris from necrosed tissue. Reactive chlorinating species produced by myeloperoxidase amplify the oxidant capacity of activated neutrophils. Plasmalogens are a major phospholipid subclass of both endothelial cells and cardiac myocytes. Recent studies have shown that plasmalogens are targeted by neutrophil-derived reactive chlorinating species that lead to the production of alpha-chloro fatty aldehydes. Results herein demonstrate that the alpha-chloro fatty aldehyde 2-chlorohexadecanal (2-ClHDA) accumulates in rat hearts subjected to left anterior descending coronary artery occlusion. Myocardia from rats subjected to surgical infarction had increased 2-ClHDA and neutrophil infiltration levels compared with myocardia from rats subjected to sham surgery. Additionally, infarcted myocardia from rats rendered neutropenic by treatments with an anti-neutrophil antibody had diminished 2-ClHDA and neutrophil infiltration levels compared with infarcted myocardia from normopenic rats; 2-ClHDA was shown to elicit myocardial damage as determined by lactate dehydrogenase release in isolated perfused rat hearts. Additionally, 2-ClHDA treatment of hearts resulted in decreased heart rate and ventricular performance. Taken together, the present results demonstrate a novel neutrophil-dependent myeloperoxidase-based mechanism that results in 2-ClHDA production in response to regional myocardial infarction that may also contribute to cardiac dysfunction.

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

“…In addition protein-derived chloramines are able to initiate secondary plasmalogen modification: The most potent are histidine chloramine analogues (with reaction kinetics only 5-to 30-fold slower than HOCl), whereas N-acetyllysine and taurine chloramines are less effective (approx 10 5 -fold slower than HOCl [42,43] We have detected substantial amounts of 2-ClHDA (2 μg/g wet brain containing approx 80% water resulting in a concentration of approx 10 μM) only in endotoxin-injected mice. These 2-ClHDA concentrations are in a range comparable to that reported for a rat model of myocardial infarction (approx 1 μM [21]) and for human atherosclerotic lesion material (approx 10 μM [7]). This provides clear evidence that MPO-dependent plasmalogen modification is a neuroinflammatory event.…”

“…These 2-ClHDA concentrations are in a range comparable to that reported for a rat model of myocardial infarction (approx 1 μM [21]) and for human atherosclerotic lesion material (approx 10 μM [7]). This provides clear evidence that MPO-dependent plasmalogen modification is a neuroinflammatory event.…”

Identification of glutathione adducts of α-chlorofatty aldehydes produced in activated neutrophils

“…␣ -ClFALD production in MPO-containing phagocytes and during infl ammatory processes has previously been described (9)(10)(11)(12). However, the mechanisms underlying the biological properties and metabolism of ␣ -ClFALD are 2-ClODA molecular species were elevated by 5 min, peak by 30 min, and begin to decline by 60 min.…”

“…Although ␣ -ClFALD accumulates in activated neutrophils, activated monocytes, human aortic atherosclerotic plaques, and infarcted rat myocardium (9)(10)(11)(12),…”

Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein

“…The most well characterized α-halofatty aldehyde is α-chlorofatty aldehyde (α-ClFALD) produced by reactions between hypochlorous acid (HOCl), derived from neutrophils, monocytes, and some tissue macrophages (3,4), and plasmalogen ( Figure 1). Production of α-ClFALD has been shown in human atherosclerotic plaques (5) and infarcted rat myocardium (6). MPO-derived α-ClFALD has also been implicated in endothelial dysfunction (7), neuronal apoptosis (8), activating the nuclear factor κB pathway, eNOS inhibition (9), neutrophil chemotaxis (3), and myocardial contractile dysfunction (6).…”