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

Chintan Gandhi; David G Motto; Melissa Jensen; Steven R Lentz; Anil K Chauhan

doi:10.1182/blood-2012-06-440255

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

Journal article

Open access

Peer reviewed

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

Chintan Gandhi, David G Motto, Melissa Jensen, Steven R Lentz and Anil K Chauhan

Blood, Vol.120(26), pp.5224-5230

12/20/2012

DOI: 10.1182/blood-2012-06-440255

PMCID: PMC3537314

PMID: 22983446

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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.

Metalloendopeptidases - genetics

Myocardial Infarction - genetics

Apoptosis - drug effects

von Willebrand Factor - immunology

Metalloendopeptidases - deficiency

Apoptosis - genetics

Male

von Willebrand Factor - genetics

Myocardial Reperfusion Injury - pathology

von Willebrand Factor - antagonists & inhibitors

von Willebrand Factor - physiology

Myocardial Infarction - pathology

Myocardial Reperfusion Injury - genetics

Mice, Inbred C57BL

Antibodies, Neutralizing - pharmacology

Cardiotonic Agents - pharmacology

ADAMTS13 Protein

Neutrophil Infiltration - genetics

Disease Progression

Mice, Knockout

Myocardial Infarction - complications

Myocytes, Cardiac - pathology

Animals

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - physiology

Myocytes, Cardiac - metabolism

Metalloendopeptidases - physiology

Mice

Apoptosis - physiology

Details

Title: Subtitle: ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice
Creators: Chintan Gandhi - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
David G Motto
Melissa Jensen
Steven R Lentz
Anil K Chauhan
Resource Type: Journal article
Publication Details: Blood, Vol.120(26), pp.5224-5230
DOI: 10.1182/blood-2012-06-440255
PMID: 22983446
PMCID: PMC3537314
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: HL063943 / NHLBI NIH HHS K08 HL076539 / NHLBI NIH HHS R01 HL106495 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS HL076539 / NHLBI NIH HHS NS024621 / NINDS NIH HHS R01 HL063943 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS
Language: English
Date published: 12/20/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094218502771

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