Lipoxygenase Products Increase Monocyte Adhesion to Human Aortic Endothelial Cells

Patricia, Mary Kim; Kim, Jeong‐A; Harper, Cynthia M.; Shih, Peggy T.; Berliner, Judith A.; Natarajan, Rama; Nadler, Jerry L.; Hedrick, Catherine C.

doi:10.1161/01.atv.19.11.2615

Cited by 113 publications

(110 citation statements)

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“…Human aortic ECs were obtained from aortic rings of explanted donor hearts [16] following approved guidelines from the University of Virginia Institutional Review Board and were maintained in culture as described [10]. Human aortic ECs were cultured in either 5.5 mmol/l D-glucose (NG), 25 mmol/l D-glucose (HG) or 5.5 mmol/l D-glucose with 19.5 mmol/l mannitol (as an osmotic control) for the times indicated.…”

Section: Methodsmentioning

confidence: 99%

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

et al. 2004

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Aims/hypothesis. Hyperglycaemia is a primary cause of vascular complications in diabetes. A hallmark of these vascular complications is endothelial cell dysfunction, which is partly due to the reduced production of nitric oxide. The aim of this study was to investigate the regulation of endothelial nitric oxide synthase (eNOS) activity by acute and chronic elevated glucose. Methods. Human aortic endothelial cells were cultured in 5.5 mmol/l (NG) or 25 mmol/l glucose (HG) for 4 h, 1 day, 3 days or 7 days. Mouse aortic endothelial cells were freshly isolated from C57BL/6J control and diabetic db/db mice. The expression and activity of eNOS were measured using quantitative PCR and nitrite measurements respectively. The binding of activator protein-1 (AP-1) to DNA in nuclear extracts was determined using electrophoretic mobility-shift assays. Results. Acute exposure (4 h) of human aortic endothelial cells to 25 mmol/l glucose moderately increased eNOS activity and eNOS mRNA and protein expression. In contrast, chronic exposure to elevated glucose (25 mmol/l for 7 days) reduced total nitrite levels (46% reduction), levels of eNOS mRNA (46% reduction) and eNOS protein (65% reduction). In addition, AP-1 DNA binding activity was increased in chronic HGcultured human aortic endothelial cells, and this effect was reduced by the specific inhibition of reactive oxygen species production through the mitochondrial electron transport chain. Mutation of AP-1 sites in the human eNOS promoter reversed the effects of HG. Compared with C57BL/6J control mice, eNOS mRNA levels in diabetic db/db mouse aortic endothelial cells were reduced by 60%. This decrease was reversed by the overexpression of manganese superoxide dismutase using an adenoviral construct. Conclusions/interpretation. In diabetes, the expression and activity of eNOS is regulated through glucosemediated mitochondrial production of reactive oxygen species and activation of the oxidative stress transcription factor AP-1. Abbreviations: AP-1, activator protein-1 · EC, endothelial cell · eNOS, endothelial nitric oxide synthase · FBS, fetal bovine serum · HG, high glucose · MnSOD, manganese superoxide dismutase · MOI, multiplicity of infection · NF-κB, nuclear factor-κB · NG, normal glucose · ROS, reactive oxygen species · UCP-1, uncoupling protein-1

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Section: Methodsmentioning

confidence: 99%

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

et al. 2004

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“…Increased formation of LO products such as 12(S)-HETE by the biological agents involved in cardiovascular dysfunction has been reported in VSMCs, endothelial cells, and monocytes (6,(13)(14)(15)22). 12(S)-HETE has direct effects like chemotaxis (23); changes in vascular tone (24); and production of vascular endothelial growth factor, a potent angiogenic agent (25).…”

mentioning

confidence: 99%

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

Reddy¹,

Thimmalapura²,

Lanting³

et al. 2002

Journal of Biological Chemistry

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Growth factor-and cytokine-induced vascular smooth muscle cell proliferation, migration, hypertrophy, and matrix production have been shown to play important roles in the development of vascular disorders such as atherosclerosis, hypertension, and restenosis. Growth factors such as angiotensin II (AngII) 1 and platelet-derived growth factor (PDGF) activate intracellular phospholipases, leading to the formation of arachidonic acid, which can be further metabolized by cyclooxygenases, cytochrome P-450 oxygenases, and lipoxygenases (1). Lipoxygenase (LO) action leads to the formation of oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). LOs and their products of arachidonic acid and linoleic acid metabolism have been shown to mediate growth factor effects in vascular smooth muscle cells (VSMCs) as well as responses to vascular injury. Lipoxygenases are classified as 5-, 8-, 12-, and 15-lipoxygenases based on their ability to insert molecular oxygen at the corresponding carbon atom of arachidonic acid. Three major isoforms of 12-LO have been cloned. They are platelet-type 12-LO, leukocyte-type 12-LO, and epidermis-type 12-LO. These proteins are products of distinct genes and vary in tissue distribution (2, 3).Leukocyte 12-LO has been cloned from porcine and mouse leukocytes (4, 5). The presence of leukocyte-type 12-LO (also termed 12/15-LO) has also been demonstrated in various cell types and tissues, including VSMCs, adrenal cells, rat brain, and kidney (6 -11). Studies from this and other laboratories (12-21) have implicated the leukocyte-type 12-LO pathway in the pathogenesis of atherosclerosis and restenosis. 12-LO expression was demonstrated in atherosclerotic lesions (12). In vascular and mononuclear cells, growth factors and cytokines as well as high glucose stimulate both the activity and expression of 12-LO (6, 13-15). Furthermore, expression of 12-LO protein and mRNA is markedly increased in neointima of balloon-injured rat carotid arteries, and pretreatment with LO inhibitors reduces the rate of neointimal thickening in this model (16,17). We have demonstrated that treatment with a chimeric DNA-RNA hammerhead ribozyme targeted to cleave rat leukocyte-type 12-LO mRNA significantly reduces neointimal thickening in balloon-injured rat arteries (18). We have

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“…33 In addition, 12/15LO is abundantly expressed in macrophages 19 and regulates processes in macrophages implicated in atherogenesis. 31,34 Indeed, disruption of the 12/15LO gene diminished atherosclerosis in ApoE Ϫ/Ϫ mice, 35 and macrophage 12/15LO has been implicated in this effect. 36 Results of the present study demonstrate that in addition to reduced atherosclerosis, DKO mice have attenuated NIF in response to injury.…”

Section: Discussionmentioning

confidence: 99%

“…Relevance for determining the impact of baseline increase in 12/15LO on vascular lesion formation is provided by several studies demonstrating that conditions associated with accelerated vascular response to injury (eg, increased oxidative stress and type 2 diabetes) are associated with enhanced 12/15LO expression. 11,18 -21 12/15LO has been implicated in mediating monocyte adhesion to endothelial cells 31,32 and VSMCs. 33 In addition, 12/15LO is abundantly expressed in macrophages 19 and regulates processes in macrophages implicated in atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Immunostaining for fibronectin in ApoE Ϫ/Ϫ and DKO mice demonstrated a trend to lower fibronectin deposition in DKO mice compared with ApoE Ϫ/Ϫ mice (supplemental Figure III). Because 12S-HETE induction of fibronectin has mediated monocyte adhesion, 30,31 injured artery sections from BL-6, 12/15LO-tg, ApoE Ϫ/Ϫ , and DKO mice were stained with an anti-MAC-2 antibody (supplemental Figure IV). Although there was increased MAC-2 staining in the mice on an ApoE Ϫ/Ϫ compared with a BL-6 background, there was no statistically significant differences in MAC-2 staining with increase or loss of 12/15LO expression (data not shown).…”

Section: Deliri Et Al 12/15lo Enhances the Vascular Response To Injurymentioning

confidence: 99%

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Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

Deliri

Meller

Kadakkal

et al. 2011

ATVB

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Objective-To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. Methods and Results-12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E Ϫ/Ϫ , ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ , C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE Ϫ/Ϫ VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21 cip1 promoter and abrogated 12/15LO-induced VSMC proliferation. Conclusion-To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Key Words: vascular biology Ⅲ fibronectin Ⅲ helix-loop-helix motifs Ⅲ lipoxygenase Ⅲ neointima Ⅲ smooth muscle cell I ndividuals with type 2 diabetes mellitus have increased rates of restenosis after vascular interventional procedures. 1,2 Vascular smooth muscle cell (VSMC) proliferation and matrix production are key events in the process of neointimal formation (NIF) after percutaneous interventions. 3,4 Identifying the molecular mechanisms that mediate acceleration of these processes may provide important insight into strategies to attenuate restenosis in high-risk populations, such as those with type 2 diabetes.Previous studies have implicated 12/15-lipoxygenase (12/ 15LO) in the vascular response to injury. 12/15LO products of arachidonic acid, such as 12S-hydroxyeicosatetrenoic acid (HETE), 15S-HETE, and 13S-hydroperoxyoctadecadienoic acid (HPODE), are produced in VSMCs and have hypertrophic effects. 5,6 In vitro, 12/15LO inhibition attenuates hypertrophic effects of angiotensin II in VSMCs, mitogenic effects of cytokines, and chemotactic effects of platelet-derived growth factor. 5,7,8 Compared with VSMCs from C57BL/6 (BL-6) mice, VSMCs from 12/15LO-overexpressing transgenic (12/15LO-tg) mice grow faster, and VSMCs from 12/15LO Ϫ/Ϫ mice grow slower and display decreased S-phase entry in culture. 9,10 12/15LO and its products are increased in the vascular wall of animal models of atherosclerosis and injury-induced restenosis. 11 Compared with uninjured carotids, 12/15LO expression is significantly increased in rat carotids on day 12 after injury. 12 Moreover, pharmacological...

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Lipoxygenase Products Increase Monocyte Adhesion to Human Aortic Endothelial Cells

Cited by 113 publications

References 44 publications

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

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