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 clinical outcomes. 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 alpha-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% (P<0.001) less LV dilation and a 52.2% (P<0.0001) 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.

• Authors: Nikolay Vasilyev, Timothy Williams, Marie-Luise Brennan, Samuel Unzek, Xiaorong Zhou, Jay W Heinecke, Douglas R Spitz, Eric J Topol, Stanley L Hazen, Marc S Penn
• Journal: Circulation (Circulation) Vol. 112 Issue 18 Pg. 2812-20 (Nov 01 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 16267254 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aldehydes
• Formaldehyde
• Acrolein
• Hydrogen Peroxide
• Peroxidase
• Glutathione
• 4-hydroxy-2-nonenal
• Glutathione Disulfide

Topics

• Acrolein (toxicity)
• Aldehydes (pharmacology)
• Animals
• Aorta
• Cattle
• Cell Line
• Cell Survival (drug effects)
• Cells, Cultured
• Formaldehyde (toxicity)
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Humans
• Hydrogen Peroxide (pharmacology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Myocardial Infarction (pathology)
• Neutrophils (physiology)
• Peroxidase (metabolism)
• Pulmonary Artery (drug effects, physiology)
• Ventricular Remodeling (drug effects, physiology)