ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice

Blood. 2012 Dec 20;120(26):5224-30. doi: 10.1182/blood-2012-06-440255. Epub 2012 Sep 14.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAMTS13 Protein
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cardiotonic Agents / pharmacology
  • Disease Progression
  • Male
  • Metalloendopeptidases / deficiency*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / complications
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / genetics*
  • Myocardial Reperfusion Injury / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Neutrophil Infiltration / genetics
  • von Willebrand Factor / antagonists & inhibitors
  • von Willebrand Factor / genetics
  • von Willebrand Factor / immunology
  • von Willebrand Factor / physiology*

Substances

  • Antibodies, Neutralizing
  • Cardiotonic Agents
  • von Willebrand Factor
  • ADAMTS13 protein, mouse
  • Metalloendopeptidases
  • ADAMTS13 Protein