Laminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells

Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and γ-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm2) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-α-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature. Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and γ-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm2) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-α-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature. vascular cell adhesion molecule-1 antioxidant response element chloramphenicol acetyltransferase glutathioneS-transferase human aortic endothelial cells human microvascular endothelial cells heme oxygenase-1 cytosolic inhibitor of Nrf2 NAD(P)H:quinone oxidoreductase-1 NF-E2-related factor-2 reactive oxygen species tumor necrosis factor-α electrophile response element reverse transcriptase Vascular endothelial cells are exposed to a tangential shearing force resulting from the flow of blood over the lumenal surface of the vessel wall (1Nerem R.M. Alexander R.W. Chappell D.C. Medford R.M. Varner S.E. Taylor W.R. Am. J. Med. Sci. 1998; 316: 169-175Crossref PubMed Scopus (170) Google Scholar). The nature and magnitude of this fluid shear stress play a key role in the maintenance of vascular integrity and in the development of vascular diseases. For example, the nonrandom distribution of atherosclerotic lesions is due at least in part to local alterations in hemodynamic forces impinging on the vasculature (2Asakura T. Karino T. Circ. Res. 1990; 66: 1045-1066Crossref PubMed Scopus (732) Google Scholar, 3Cornhill J.F. Akins D. Hutson M. Chandler A.B. Atherosclerosis. 1980; 35: 77-86Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 4Montenegro M.R. Eggen D.A. Lab. Invest. 1968; 18: 586-593PubMed Google Scholar). At sites vulnerable to lesion formation such as branch points, bifurcations, and curvatures, unidirectional laminar flow is disturbed, with areas characterized by complex flow patterns such as nonlaminar flow and flow reversal. In contrast, lesion-protected areas of the vasculature are characterized by more uniform laminar flow patterns with relatively high levels of fluid shear stress (2Asakura T. Karino T. Circ. Res. 1990; 66: 1045-1066Crossref PubMed Scopus (732) Google Scholar, 3Cornhill J.F. Akins D. Hutson M. Chandler A.B. Atherosclerosis. 1980; 35: 77-86Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 4Montenegro M.R. Eggen D.A. Lab. Invest. 1968; 18: 586-593PubMed Google Scholar). It is now well accepted that areas of the vasculature exposed to nonlaminar or oscillatory flow have a predilection for the development of atherosclerotic lesions, whereas relatively high levels of steady laminar flow are athero-protective. Differential regulation of endothelial gene expression by shear stress may be involved in the focal localization of early atherosclerotic lesions (5Resnick N. Gimbrone M.A., Jr. FASEB J. 1995; 9: 874-882Crossref PubMed Scopus (473) Google Scholar). For example, pro-atherogenic genes such as platelet-derived growth factor and monocyte chemoattractant protein-1 are transiently up-regulated by shear stress, peak at 1.5 h, and are followed by sustained down-regulation (6Shyy Y.J. Hsieh H.J. Usami S. Chien S. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4678-4682Crossref PubMed Scopus (324) Google Scholar, 7Hsieh H.J., Li, N.Q. Frangos J.A. Am. J. Physiol. 1991; 260: H642-H646PubMed Google Scholar). These initial responses of cultured endothelial cells to applied shear stress may reflect in vivo responses to the temporal and spatial changes of shear stress resulting from nonlaminar flow. Prolonged exposure of endothelial cells to oscillatory flow results in up-regulation of vascular cell adhesion molecule-1 (VCAM-1),1 intercellular adhesion molecule-1, and E-selectin (8Chappell D.C. Varner S.E. Nerem R.M. Medford R.M. Alexander R.W. Circ. Res. 1998; 82: 532-539Crossref PubMed Scopus (471) Google Scholar), suggesting that oscillatory flow imparts a proinflammatory phenotype in endothelial cells. In contrast, physiological levels of laminar flow are anti-inflammatory and anti-adhesive. Prolonged exposure of murine endothelial cells to laminar flow results in down-regulation of the expression of VCAM-1, intercellular adhesion molecule-1, and E-selectin (9Korenaga R. Ando J. Kosaki K. Isshiki M. Takada Y. Kamiya A. Am. J. Physiol. 1997; 273: C1506-C1515Crossref PubMed Google Scholar). We reported that chronic laminar flow suppresses interleukin-1β-induced VCAM-1 gene expression in endothelial cells (1Nerem R.M. Alexander R.W. Chappell D.C. Medford R.M. Varner S.E. Taylor W.R. Am. J. Med. Sci. 1998; 316: 169-175Crossref PubMed Scopus (170) Google Scholar). 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Full Text PDF PubMed Google Scholar). the of have identified genes whose expression is by prolonged exposure to laminar flow as with in human aortic endothelial cells In the that exposure of endothelial cells to laminar flow activates transcriptional and the expression of a set of These genes microsomal epoxide hydrolase, and γ-glutamylcysteine We demonstrate that the ARE is the element in the promoter of the NQO1 and HO-1 genes that laminar flow-induced gene ARE-dependent NQO1 gene regulation in endothelial cells the transcriptional factor NF-E2-related factor Furthermore, of NQO1 or Nrf2 inhibited activation of VCAM-1 gene These data that laminar flow may athero-protective a in expression of antioxidant genes in endothelial cells. this laminar may to the of that in vascular including the expression of gene from and cultured in growth and microvascular endothelial cells Medford R.M. Circ. 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The and to activity. or the of the or in and to for a to the against the activity. genes that by exposure to laminar from in or to laminar flow (shear stress = 20 dyn/cm2) for from identified by and from for sequence identified genes that relatively in the laminar with the of the promoters of a of genes including ferritin (heavy and light chains), microsomal epoxide hydrolase, and γ-glutamylcysteine a transcriptional regulatory of genes an ARE or ARE-like transcriptional regulatory in promoter and is to be up-regulated by stress. Furthermore, genes function as antioxidants and protect cells from stress. the sequence of the ARE or ARE-like regulatory from the laminar genes with the ARE 1994; PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). These the that the may laminar flow-induced gene expression in endothelial sequence of from laminar flow NQO1 T. Y. J. 1995; Full Text Full Text PDF PubMed Scopus Google ferritin (heavy T. Y. 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A. 1997; 94: PubMed Scopus Google in a results from the that laminar flow the expression of levels by in of the genes to by exposure to laminar flow for These that exposure of to laminar flow for results in expression of genes with the role of fluid flow in the regulation of ARE-mediated gene on the NQO1 and HO-1 The of flow and of flow for their to NQO1 gene in the expression of NQO1 in response to laminar flow from to Similarly, the expression of HO-1 in response to laminar flow from to In contrast, the levels of NQO1 and HO-1 in relatively the in the expression of NQO1 in response to laminar flow at on the levels of shear stress. with laminar flow with shear stress of the NQO1 levels the shear stress to 20 in an in NQO1 levels at These data demonstrate that levels of shear stress in expression of NQO1 in endothelial on NQO1 expression in endothelial cells. in or to oscillatory flow with shear stress at or laminar flow with shear stress at or 20 for NQO1 levels by and by gene are = with with the oscillatory flow endothelial cell genes are in response to either laminar or nonlaminar flow. flow is to an phenotype to the whereas nonlaminar flow or oscillatory flow imparts a oxidant stress and a more We the of oscillatory flow and laminar flow on NQO1 gene expression at in exposure of for to oscillatory flow with shear stress of induced a in NQO1 the magnitude of with the more in with laminar flow of the magnitude of shear stress These results that the flow the of shear stress NQO1 gene expression in endothelial cells. We the of laminar or oscillatory flow on NQO1 levels by in exposure of for to oscillatory flow (shear stress = dyn/cm2) in an in NQO1 with of to laminar flow (shear stress = 20 dyn/cm2) induced a in NQO1 with These data the results with NQO1 levels that physiological levels of laminar flow are a of genes such as laminar flow the expression of a set of genes that contain the ARE regulatory that the ARE or ARE-like may represent a novel and element that expression in response to shear stress. that the ARE as a shear transcriptional transiently with and cells to laminar flow (shear stress = 20 dyn/cm2) for gene of the ARE from the NQO1 to a are relatively to to laminar flow induced the expression of genes in in laminar flow of in a in the promoter activity. In contrast, of the to abolished laminar flow-induced promoter activity. These data demonstrate that the ARE is a identified shear stress response element in endothelial cells. the role of the ARE in laminar flow-induced gene with the and ARE NQO1 or HO-1 The data in demonstrate that exposure of for to laminar flow in activation of the NQO1 In contrast, with of the ARE in the NQO1 activation by laminar flow Similarly, exposure of for to laminar flow HO-1 promoter of the ARE in the HO-1 promoter abolished laminar flow-induced HO-1 promoter These demonstrate that laminar flow activation of the NQO1 and HO-1 genes in endothelial cells at the transcriptional activation of NQO1 and HO-1 by laminar flow a ARE element. data that the ARE transcriptional element is an of in endothelial cells by exposure to shear stress. Nrf2 is a and transcriptional factor and a role in ARE-mediated gene expression K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. K. J. T. T. T. M. Sci. 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These genes contain ARE or ARE-like transcriptional regulatory in their For the that the ARE a transcriptional element to shear stress in endothelial cells. demonstrate that activation of genes the transcriptional factor Nrf2 or via of of the expression of the adhesion VCAM-1, in endothelial cells. These a novel mechanism that the athero-protective and antioxidant nature of laminar flow. of the ARE and and genes by laminar flow to to protect against endothelial and gene that fluid shear stress endothelial gene expression including the element Y. M. Chien S. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar), the shear stress response element N. T. Jr. Gimbrone M.A., Jr. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), T. N. Jr. Gimbrone M.A., Jr. PubMed Scopus Google Scholar, Frangos J.A. PubMed Scopus Google Scholar, S. N. Am. J. Physiol. PubMed Google Scholar), and an early growth element T. N. 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