| مستخلص: |
Atherosclerosis is a chronic inflammatory disease. Several proinflammatory mediators including (LPS and TNFαa) activate EC by simultaneously activating dual NF-KB and MAP kinase signalling pathways. The activity of p38 and JNK MAP Kinases is tightly controlled in EC by several negative regulators including MAPK phosphatase1 (MKP- 1) and the transcription factor Nrf2. Blood flow exerts several mechanical forces on endothelial surfaces including pressure, circumferential stretch, and shear stress (mechanical drag). It is widely believed that shear stress plays a central role in the pathogenesis of atherosclerosis as lesions predominate at regions exposed to disturbed flow that is associated with low shear stress while regions exposed to high shear stress are protected. MKP-1 is a central mediator of the anti-inflammatory effects of shear stress. Studies using cultured human umbilical vein EC (HUVEC) revealed that MKP-1 is induced by prolonged high shear stress. In-vivo studies of murine aortae by en face staining showed that MKP-1 is expressed at atheroprotected sites which are exposed to high shear stress but not at atherosusceptible sites. The assessment of the functional role of MKP1 in-vivo was carried out by comparing wild type and MKP-1/- C57BL/6 mice which revealed that MKP-1 is necessary for the suppression of p38 and JNK activity, and VCAM-1 expression at atheroprotected sites as the genetic deletion of MKP-1 can lead to the loss of protection at these sites. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites. The identification of transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1(-/-), and MKP-1(-/-) mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1. Nrf2 is also essential for the suppression of endothelial activation by high shear. The activation of Nrf2 at atherosusceptible sites of murine aortae by sulforaphane (a dietary antioxidant that acts as a potent activator of Nrf2) suppressed p38 activation and VCAM-1 expression in cultured EC. In-vivo studies showed that the administration of sulforaphane increased Nrf2 activity and reduced p38 activation and VCAM-1 expression at the atherosusceptible sites of wild type but had no effect on Nrf2-/- C57BL/6 mice. [ABSTRACT FROM AUTHOR] |
