Protective Role of ADAMTS13 for Myocardium in Mouse Model of Experimental Myocardial Infarction.

Abstract 2175

The metalloprotease ADAMTS13 regulates the size of von Willebrand factor (VWF) multimers, controlling excessive VWF functions and preventing thrombotic occlusion of microvasculature. We previously reported that ADAMTS13 deficiency aggravated the extent of brain ischemic stroke in a mouse model of middle cerebral arterial occlusion, suggesting the relevant role of ADAMTS13 in the pathophysiology of brain stroke (Fujioka, et al. Blood, 2010; 115: 1650). These results raised the possibility that the functional regulation of VWF by ADAMTS13 could also play a role in coronary ischemic events such as myocardial infarction. To address this issue, we have used a mouse model of experimental myocardial infarction. The left anterior descending coronary artery in mice was ligated at 2 mm downstream from the origin under thoracotomy with ventilator-assisted respiration, and the cardiac function was evaluated with M-mode echocardiography after 7 days of operation. We compared 20 wild-type (WT) mice and 20 Adamts13 −/− (KO) mice, all of which were 12–14 weeks of age, healthy and fertile. Significantly (p < 0.01) decreased ejection fraction (EF; 44.0±6.7%) and increased left ventricular end-diastolic diameter (LVDd; 4.68±0.69 mm) of KO mice, as compared to WT (EF; 62.7±13.0% and LVDd; 3.77±0.56 mm, respectively), revealed that cardiac functions were apparently more impaired in KO mice. In addition, these reduced cardiac functions observed in KO mice were improved to an extent comparable to those of WT mice by the bolus injection of recombinant human ADAMTS13 (rhADAM; 3 μg/mouse, n=20) just after the operation (KO mice + rhADAM, EF; 58.2.±9.9% and LVDd; 3.16±0.52 mm). Consistent with echocardiography data, histological studies demonstrated the significantly (p < 0.01) higher infarct ratio in myocardium of KO mice (WT; 37.3±18.4%, KO; 59.1±16.3%, KO + rhADAM; 33.7±24.4%). Our results indicate that ADAMTS13, as seen in the case of brain ischemic stroke, plays a protective role for myocardium in coronary artery ischemia, improving myocardial functions and the severity of heart failure. Proper functional regulation of VWF-dependent thrombotic or inflammatory responses by ADAMTS13 could reduce thrombotic occlusion of microvasculature including leukocyte plugging, contributing to better local microcirculation which is crucial for tissue or organ functions.