Objective-Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. Methods and Results-Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1␣, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. Key Words: epoxyeicosatrienoic acids Ⅲ soluble epoxide hydrolase Ⅲ dyslipidemia Ⅲ atherosclerosis Ⅲ abdominal aorta aneurysm Ⅲ inflammatory markers A rachidonic acid can be metabolized by 3 major oxidative pathways: cyclooxygenase (COX) forming prostaglandins; lipoxygenase (LOX) forming hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and cytochrome P-450 monooxygenase forming epoxides and HETEs. 1 The COX and LOX pathways have been extensively studied, and their eicosanoid products have been shown to play important roles in a variety of biological processes such as inflammation, cell proliferation, and intracellular signaling. In contrast, less is known about the "third pathway" of arachidonic acid metabolism. Recently, epoxyeicosatrienoic acids (EETs), the cytochrome P450 metabolites of arachidonic acid, have received increasing attention for multiple beneficial biological functions, including vasodilation, antiinflammation, and inhibition of proliferation and migration of vascular smooth muscle cells. 1,2 Based on these properties, it has been postulated that EETs may exert therapeutic benefits in inflammatory vascular diseases, such as atherosclerosis. 2,3 Soluble epoxide hydrolase (s-EH) converts EETs into their corresponding dihydroxyeicosatrienoic acids (DHETs), which are generally thought to have reduced biological activity relative to EETs, and hydration of the EETs by s-EH is a dominant mechanism whereby their activity can be reduced. 4 Thus, inhibition of s-EH could be a promising therapeutic target for amplifying the beneficial effects of EETs. 4 Indeed, s-EH inhibitors have been demonstrated to lower blood pressure in hypertension, 5,6 decrease hypertension-induced renal damage 7 and cerebral ischemia injury, 8 attenuate vascular smooth muscle cell proliferation, 9 and reduce tissue...

No abstract

Murine collagen-induced arthritis (CIA) has become a valuable animal model for elucidating pathogenic mechanisms and evaluating therapeutic effects for rheumatoid arthritis. Recent advances in digital imaging and computer technology have enabled gait analysis to develop into a powerful tool for objectively detecting functional deficits in human and animal models. The present study explored the use of non-invasive video-capture gait analysis in the evaluation of a murine CIA model. CIA was induced in 45 female DBA/1LacJ mice (8 to 10 weeks old) by immunization with lyophilized bovine articular type II collagen. Gait parameters were determined by ventral plane videography and were correlated to traditional arthritis clinical scores. Our results showed that increases in clinical scores that measure the severity of CIA corresponded to changes in multiple gait parameters that reflect both morphologic (increases in paw area) and functional (increase in stride frequency, decrease in stride length, hind-limb paw placement angle, as well as stride, stance, and braking times) deficits. Our work indicated that the non-invasive video-capture device may be used as a simple and objective data acquisition system for quantifying gait disturbances in CIA mice for the investigation of mechanisms and the evaluation of therapeutic agents.

No abstract

No abstract