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

• Published in: Blood Vol. 120; no. 26; pp. 5224 - 5230
• Main Authors: Gandhi, Chintan, Motto, David G., Jensen, Melissa, Lentz, Steven R., Chauhan, Anil K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2012; American Society of Hematology
• Subjects: 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; Thrombosis and Hemostasis; Vascular Biology; von Willebrand Factor - antagonists & inhibitors; von Willebrand Factor - genetics; von Willebrand Factor - immunology; von Willebrand Factor - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-06-440255

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.