Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction

Arman T. Askari, Marie Luise Brennan, Xiaorong Zhou, Jeanne Drinko, Annitta Morehead, James D. Thomas, Eric J. Topol, Stanley L. Hazen, Marc S. Penn*

*Corresponding author for this work

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO-/-). MPO-/- demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO-/-, leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO-/- and accelerated rupture in the PAI-1-/-. These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalJournal of Experimental Medicine
Volume197
Issue number5
DOIs
StatePublished - Mar 3 2003

Keywords

  • Chlorination
  • Free radical
  • Inflammation
  • Myocardial rupture
  • Protease activation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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