Objective-Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries. Methods and Results-En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38 -VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38 -VCAM-1 signaling at the susceptible site in wild-type but not Nrf2 Ϫ/Ϫ animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1. Key Words: Nrf2 Ⅲ arterial endothelium Ⅲ shear stress Ⅲ sulforaphane Ⅲ proinflammatory activation Ⅲ p38 Ⅲ MKK3/6 Ⅲ MKP-1 E arly atherosclerotic lesions contain monocytes and T-lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (ECs). 1 This process is triggered by proinflammatory mediators (eg, TNF␣) which induce cellular adhesion molecules (eg, VCAM-1) via signaling intermediaries including p38 mitogen-activated protein (MAP) kinase, which is activated by phosphorylation by MAP kinase kinases 3 and 6 (MKK 3/6). 2,3 Vascular inflammation and atherosclerosis develop predominantly at distinct sites of the arterial tree located near branches and bends which are exposed to nonuniform blood flow, which exerts relatively low shear stress on vascular endothelium, whereas regions of arteries that are exposed to unidirectional high shear stress are protected. 4 -6 Proinflammatory activation of ECs is reduced at high-shear sites compared to low-shear regions, thus providing a potential explanation for the distinct spatial localization of vascular inflammation and lesion formation. 5,7-10 Similarly, the application of unidirectional high shear stress can suppress proinflammatory activation of cultured ECs, whereas low or oscillatory shear can act as a positive regulator of EC activation. 5,10 -15 The molecular mechanisms underlying the antiinflammatory effects of shear stress are uncertain, but previous studies of cultured cells have suggested a role for the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). 16 -20 In unstimulated cells, Nrf2 is suppressed by kelch-like ECH-associated protein 1 (Keap1) which targets it for ubiquitination and proteasomal processing. Nrf2 can be activated by shear stress, dietary antioxidants (eg, sulforaphane) and other physiological stimuli which disrupt Keap1-Nrf2 interactions leading to stabilization and nuclear translocation of Nrf2. 16 -22 A previous study...

Reactive arthritis is an important cause of lower limb oligoarthritis, mainly in young adults. It is one of the spondyloarthropathy family; it is distinguishable from other forms of inflammatory arthritis by virtue of the distribution of affected sites and the high prevalence of characteristic extra-articular lesions. Many terms have been used to refer to this and related forms of arthritis leading to some confusion. Reactive arthritis is precipitated by an infection at a distant site and genetic susceptibility is marked by possession of the HLA-B27 gene, although the mechanism remains uncertain. Diagnosis is a two stage process and requires demonstration of a temporal link with a recognised "trigger" infection. The identification and management of "sexually acquired" and "enteric" forms of reactive arthritis are considered. Putative links with HIV infection are also discussed. The clinical features, approach to investigation, diagnosis, and management of reactive arthritis are reviewed.

In addition to cholesterol-lowering properties, statins exhibit lipid-independent immunomodulatory, anti-inflammatory actions. However, high concentrations are typically required to induce these effects in vitro, raising questions concerning therapeutic relevance. We present evidence that endothelial cell sensitivity to statins depends upon shear stress. Using heme oxygenase-1 expression as a model, we demonstrate differential heme oxygenase-1 induction by atorvastatin in atheroresistant compared with atheroprone sites of the murine aorta. In vitro, exposure of human endothelial cells to laminar shear stress significantly reduced the statin concentration required to induce heme oxygenase-1 and protect against H 2 O 2 -mediated injury. Synergy was observed between laminar shear stress and atorvastatin, resulting in optimal expression of heme oxygenase-1 and resistance to oxidative stress, a response inhibited by heme oxygenase-1 small interfering RNA. Moreover, treatment of laminar shear stress-exposed endothelial cells resulted in a significant fall in intracellular cholesterol. Mechanistically, synergy required Akt phosphorylation, activation of Kruppel-like factor 2, NF-E2-related factor-2 (Nrf2), increased nitric-oxide synthase activity, and enhanced HO-1 mRNA stability. In contrast, heme oxygenase-1 induction by atorvastatin in endothelial cells exposed to oscillatory flow was markedly attenuated. We have identified a novel relationship between laminar shear stress and statins, demonstrating that atorvastatin-mediated heme oxygenase-1-dependent antioxidant effects are laminar shear stress-dependent, proving the principle that biomechanical signaling contributes significantly to endothelial responsiveness to pharmacological agents. Our findings suggest statin pleiotropy may be suboptimal at disturbed flow atherosusceptible sites, emphasizing the need for more specific therapeutic agents, such as those targeting Kruppel-like factor 2 or Nrf2.The efficacy of 3-hydroxy-3-methylglutaryl-coenzyme A reductase antagonists (statins) in reducing low density lipoprotein cholesterol, cardiovascular morbidity, and mortality is widely recognized (1). The observation that beneficial actions of statins on vascular function are detectable prior to any fall in serum cholesterol, extend to normocholesterolemic patients and exceed those of other lipid-lowering drugs despite comparable falls in total cholesterol (2, 3), suggest the existence of low density lipoprotein-cholesterol-independent effects (4, 5). Judging from in vitro studies, these may include immunomodulatory, antiinflammatory, anti-adhesive, anti-thrombotic, and cytoprotective actions (6). However, the experimental work demonstrating these pleiotropic effects has predominantly used statin concentrations exceeding those achieved by therapeutic dosing, raising questions concerning clinical relevance (4).Heme oxygenase-1 (HO-1) 2 acts as the rate-limiting factor in the catabolism of heme into biliverdin, releasing free iron and carbon monoxide (CO). Biliverdin is subs...