title: ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice.
abstract: Epidemiologic studies suggest that elevated VWF levels and reduced ADAMTS13 activity in the plasma are risk factors for myocardial infarction. However, it remains unknown whether the ADAMTS13-VWF axis plays a causal role in the pathophysiology of myocardial infarction. In the present study, we tested the hypothesis that ADAMTS13 reduces VWF-mediated acute myocardial ischemia/reperfusion (I/R) injury in mice. Infarct size, neutrophil infiltration, and myocyte apoptosis in the left ventricular area were quantified after 30 minutes of ischemia and 23.5 hours of reperfusion injury. Adamts13(-/-) mice exhibited significantly larger infarcts concordant with increased neutrophil infiltration and myocyte apoptosis compared with wild-type (WT) mice. In contrast, Vwf(-/-) mice exhibited significantly reduced infarct size, neutrophil infiltration, and myocyte apoptosis compared with WT mice, suggesting a detrimental role for VWF in myocardial I/R injury. Treating WT or Adamts13(-/-) mice with neutralizing Abs to VWF significantly reduced infarct size compared with control Ig-treated mice. Finally, myocardial I/R injury in Adamts13(-/-)/Vwf(-/-) mice was similar to that in Vwf(-/-) mice, suggesting that the exacerbated myocardial I/R injury observed in the setting of ADAMTS13 deficiency is VWF dependent. These findings reveal that ADAMTS13 and VWF are causally involved in myocardial I/R injury.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Chintan
authors.initials: C
authors.lastname: Gandhi
authors.forename: David G
authors.initials: DG
authors.lastname: Motto
authors.forename: Melissa
authors.initials: M
authors.lastname: Jensen
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lentz
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D018450:Disease Progression; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D020556:Neutrophil Infiltration / Q000235:genetics; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D002316:Cardiotonic Agents; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein