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¹ Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195
² Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195
³ Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, OH 44195

Address correspondence to Marc S. Penn, Director, Experimental Animal Laboratory, Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic Foundation, NC10, Cleveland, OH 44195. Phone: 216-444-7122; Fax: 216-444-9404; E-mail: pennm{at}ccf.org

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.

Key Words: myocardial rupture • free radical • chlorination • inflammation • protease activation

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