Gender-Dependent Up-Regulation of the VWF-Cleaving metalloprotease ADAMTS-13 in Mice with Obesity and Hypercholesterolemia.

The development of atherothrombosis is associated with hypercholesterolemia and systemic inflammation. Recent studies have shown that adipose tissue may directly promote inflammation. Since one of the hallmark events of atherosclerosis is the deposition of von Willebrand factor (VWF) on vascular endothelial cells, the release and proteolysis of ultra-large (UL) and hyperreactive VWF may play an important role in the development of thrombotic diseases. We therefore investigated how the synthesis of ADAMTS-13, the newly characterized metalloprotease that cleaves the hyperreactive ULVWF to smaller and less active form, may be regulated in mice with obesity and hypercholesterolemia. Wild-type C57BL/6 and Apo E −/− C57Bl/6 mice (18 in each group with equal gender distribution) were fed with regular Chow or western-type high fat diet for 6 months and then analyzed for ADAMTS-13 mRNA in the liver (by quantitative PCR), the primary site of ADAMTS-13 synthesis, and ADAMTS-13 activity under flow condition. We found that ADAMTS-13 mRNA was more than doubled for wild-type mice on high fat diet than those on regular diet (4.14±0.46 vs. 1.72±0.57 units, respectively, p < 0.01). The increase was 47.9% for Apo E−/− mice on high fat diet compared to mice on regular diet (2.61±0.31 vs. 3.86±0.72 units, respectively, p = 0.05). When the data were stratified for gender difference, the increase was primarily observed in male mice. For male mice, ADAMTS-13 mRNA on high fat diet was more than four and two folds of those on regular diet for wild-type and Apo E−/− mice, respectively. , For female mice, however, the increase was less than 40% and only detected in wild-type mice fed with high fat diet. Consistent with this observation, ADAMTS-13 activity in general was lower in female (61±12%) than males (81±10%, p < 0.05). For both wild-type and Apo E−/− mice, we detected no difference in ADAMTS-13 activity in males, but a significantly lower activity in the female Apo E−/− mice on high fat diet (19.6±10.5% vs. 49.1±9.2% for high fat and regular diets, respectively, p < 0.05). These results demonstrate that the synthesis of ADAMTS-13 is up-regulated in obese mice (wild-type on high fat diet) and mice with hypercholesterolemia (Apo E−/− mice on high fat diet). The increase may serve as a protective measure to encounter the likely increase in ULVWF release due to systemic inflammation and endothelial cell stimulation seen in these mice. Interestingly, male mice showed a much stronger up-regulation than females. The low rate of ADAMTS-13 synthesis may contribute to the lower ADAMTS-13 activity found in female mice, suggesting that the machinery of ULVWF proteolysis in female mice may be less responsive to obesity/hypercholesterolemia and systemic inflammation.