Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling but Not Infarct Size After Myocardial Infarction

Abstract

Background-Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinicaloutcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common ␣-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. Methods and Results-In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (PϽ0.001) less LV dilation and a 52.2% (PϽ0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. Conclusions-The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function. (Circulation. 2005;112:2812-2820.)

Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion

“…Moreover, the observed increase in apoptosis in Mpo Ϫ/Ϫ mice is similar to the rise of apoptosis in WT animals during this early phase of reperfusion. Similarly, studies by Vasilyev and colleagues 19 could not show a significant contribution for MPO or its derived oxidants in the induction of apoptosis and necrosis in vivo. MPO rather adversely influenced organ function by the production of cytotoxic aldehydes 19 or the oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1).…”

“…Similarly, studies by Vasilyev and colleagues 19 could not show a significant contribution for MPO or its derived oxidants in the induction of apoptosis and necrosis in vivo. MPO rather adversely influenced organ function by the production of cytotoxic aldehydes 19 or the oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1). 39 The present data indeed suggest that MPO has no significant in vivo role in the induction of renal cell death throughout the first moments of I/R but rather has a profound effect on organ function during late reperfusion, known as progression phase.…”

“…However, there are clinical studies indicating a potentially harmful effect of MPO in immune-mediated inflammatory syndromes, such as multiple sclerosis, 12 acute coronary syndrome, 13,14 and renal disease. 15 In addition, a considerable line of research indicates that MPO and MPO-derived oxidants are involved in the pathogenesis of atherosclerosis, 16 -18 organ damage after myocardial I/R and infarction, 19 as well as complement activation in vitro. 20 Furthermore, MPO contributes to the dysfunction of the local vasculature during acute inflammation by modifying local NO production and availability.…”

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Treatment of threonine with HOCl also generated acrolein and 2-hydroxypropanal. In a murine model of acute myocardial infarction, myeloperoxidase was found to be a major enzymatic source of acrolein, as demonstrated by a dramatic increase of acrolein in ischemic cardiac tissue obtained from wild-type mice as compared to myeloperoxi-dase-deficient (MPO null) mice [48]. The authors also observed that the MPO-null mice showed better cardiac function 24 days after the ischemic injury.…”

Interindividual variability of atorvastatin treatment influence on the MPO gene expression in patients after acute myocardial infarction.

“…Myeloperoxidase (MPO) -enzyme released from activated neutrophils and monocytes during inflammation -is involved in the promotion of atherosclerosis, the destabilization of atherosclerotic plaque and the pathogenesis of ACS (Nicholls et al, 2005;Tsimikas et al, 2006;Ndrepepa et al, 2011). MPO deposition has been shown in a murine model of acute myocardial infarction (AMI) to be increased near the sites of myocardial rupture (Vasilyev et al, 2005). MPO is one of the important elements in the generation of oxidative stress and the pro-inflammatory stage progress (Zhang et al, 2001).…”