Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction.
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.
Askari
Arman T
AT
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Brennan
Marie-Luise
ML
Zhou
Xiaorong
X
Drinko
Jeanne
J
Morehead
Annitta
A
Thomas
James D
JD
Topol
Eric J
EJ
Hazen
Stanley L
SL
Penn
Marc S
MS
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003326:Coronary Circulation; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D015996:Survival Rate; D013997:Time Factors; D020257:Ventricular Remodeling
D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D003094:Collagen; D009195:Peroxidase; D017493:Leukocyte Common Antigens; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9