Objective-The goal of this study was to examine the functional relationship between aging endothelium and thrombogenicity in a mouse model of premature aging. Methods and Results-Coagulation tests and factors, blood cell counts, aorta endothelial function, aorta gene expression, and FeCl 3 -induced thrombosis in mesenteric blood vessels were analyzed in 10-to 30-week-old brain and muscle ARNT-like protein-1 (Bmal1)-deficient (knockout [KO]) mice and wild-type littermates. Ten-week-old KO mice manifested shortened prothrombin times (9.7 versus 11.3 seconds in wild-type) and elevated plasma fibrinogen (264 versus 172 mg/dL). At 30 weeks, factor VII (198% versus 149%), and platelet counts (2049 versus 1354 K/L) were increased in KO mice. Gene deficiency reduced the vasoactive nitric oxide production at 10 and 30 weeks and tended to reduce and increase the protein expression of thrombomodulin and von Willebrand factor, respectively, with aging. Shortened venular and arteriolar occlusion times on FeCl 3 -induced injury in 10-week-old KO mice confirmed higher thrombogenicity, culminating in priapism, observed in 60% of 25-to 30-week-old KO males. Conclusion-Endothelial dysfunction and a hypercoagulable state cause early arterial and venous thrombogenicity inBmal1 KO mice. With aging, progressive endothelial dysfunction, rising platelet counts, and high factor VII further enhance thrombogenicity, provoking priapism. Key Words: circadian rhythm Ⅲ coagulation Ⅲ elderly Ⅲ endothelial function Ⅲ thrombosis T he incidence of cardiovascular thrombotic complications increases dramatically with age. 1 Advanced age leads to a state of hypercoagulability in the blood, raising the relative risk for deep vein thrombosis from Ϸ1/10,000 at the age of 40 to 1/100 at the age of 80. 2 Hypercoagulability in the blood of the elderly likely results from elevation of plasma coagulation factors VII (FVII), FVIII, and FXIII; plasma levels of plasminogen activator inhibitor 1, an inhibitor of fibrinolysis, also increase. 1 Procoagulant changes are not accompanied by a proportional parallel rise in plasma levels of natural anticoagulant factors, such as proteins C and S, ie, the hemostatic balance between pro-and anticoagulant pathways is shifted toward an elevated risk for deep vein thrombosis. 2 Shear stress-modulated von Willebrand factor (VWF), present in endothelial cells and subendothelium, is a potent platelet agonist, and elevated levels are a risk factor for atherothrombosis. 3 It increases with age, a phenomenon believed to primarily reflect endothelial dysfunction. There is, however, still controversy over whether platelet function is affected by aging. 1,4 Although VWF and FVIII are independent risk factors for atherothrombotic disease, 3 the functional relationship between atherothrombosis and modifications in the aging endothelium is not fully understood. 5 See accompanying article on page 2361Arterial aging is associated with increased collagen deposition, thickening of the intima-media of the human carotid artery (2-to 3-fo...

No abstract

ObjectiveA potential strategy to treat obesity – and the associated metabolic consequences – is to increase energy expenditure. This could be achieved by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or the induction of browning of white adipose tissue (WAT). Over the last years, it has become clear that several metalloproteinases play an important role in adipocyte biology. Here, we investigated the potential role of ADAMTS5.MethodsMice deficient in ADAMTS5 (Adamts5−/−) and wild-type (Adamts5+/+) littermates were kept on a standard of Western-type diet for 15 weeks. Energy expenditure and heat production was followed by indirect calorimetry. To activate thermogenesis, mice were treated with the β3-adrenergic receptor (β3-AR) agonist CL-316,243 or alternatively, exposed to cold for 2 weeks.ResultsCompared to Adamts5+/+ mice, Adamts5−/− mice have significantly more interscapular BAT and marked browning of their subcutaneous (SC) WAT. Thermogenic pathway analysis indicated, in the absence of ADAMTS5, enhanced β3-AR signaling via activation of the cAMP response element-binding protein (CREB). Additional β3-AR stimulation with CL-316,243 promoted browning of WAT in Adamts5+/+ mice but had no additive effect in Adamts5−/− mice. However, cold exposure induced more pronounced browning of WAT in Adamts5−/− mice.ConclusionsThese data indicate that ADAMTS5 plays a functional role in development of BAT and browning of WAT. Hence, selective targeting of ADAMTS5 could provide a novel therapeutic strategy for treatment/prevention of obesity and metabolic diseases.