Anti-inflammatory effects of hemodynamic shear stress: Roles for the glucocorticoid receptor and nitric oxide
Atherosclerosis is a chronic inflammatory disease that develops in the vasculature under the influence of hemodynamic and biochemical signals. Lesions occur preferentially at regions of disturbed flow at vessel bifurcations (low shear stress), while uniform laminar flow on the endothelium (high shear stress) protects it from developing atherosclerosis. On the other hand, glucocorticoids such as dexamethasone are potent gene regulators and help combat inflammatory and immune responses. This study aims to examine the anti-inflammatory mechanisms of shear stress, including hemodynamic activation of the glucocorticoid receptor (GR) using human and bovine aortic endothelial cells (HAEC, BAEC) exposed to shear in parallel plate flow chambers. Shear stress activates the GR pathway comparable to induction with high dose dexamethasone. In BAEC and fibroblast cells expressing green fluorescent GFP-GR chimeric protein, shear stress of 10 or 25 dynes/cm2 caused rapid, distinct nuclear localization of GFP-GR. Promoter construct studies indicated shear induced expression of reporter gene from a glucocorticoid response element (GRE) promoter. Western blots demonstrated nuclear translocation of endogenous GR in sheared BAEC, and in human internal mammary artery, endothelial GR is highly nuclear localized. In HAEC, arterial shear stress of 10 dyne/cm2 blocked by more than 80% the induction by TNFα of interleukin-8 (IL-8) and IL-6 secretion. The reduction is significant even in the presence of nitric oxide synthase inhibitor. Exposure of TNFα-stimulated HAEC to arterial shear stress for 5 hr reduced by 60% the conversion of neutrophil rolling to firm arrest in a venous flow assay. Number of rolling neutrophils and rolling lengths are significantly higher for sheared than static TNFα-treated HAEC. The NO donor diethylenetriamine also significantly reduced TNFα induction of IL-8 and IL-6, and induced nuclear localization of GFP-GR and transcriptional activation from GRE promoter dose dependently. In summary, we report a new shear responsive transcriptional element, GRE. This fording correlates the anti-inflammatory functions of GR with the athero-protective effects of unidirectional arterial shear stress. Further anti-inflammatory effects of hemodynamic forces on TNFα activated endothelium include inhibition of cytokine release and reduced neutrophil attachment, processes that implicate the involvement of NO, GR, and interactions with the pro-inflammatory NFκB pathway. ^
Julie Ying Hui Ji,
"Anti-inflammatory effects of hemodynamic shear stress: Roles for the glucocorticoid receptor and nitric oxide"
(January 1, 2004).
Dissertations available from ProQuest.