Pulsatile Stretch Stimulates Superoxide Production and Activates Nuclear Factor-κB in Human Coronary Smooth Muscle

Hishikawa, Keiichi; Oemar, Barry S.; Yang, Zhihong; Lüscher, Thomas F.

doi:10.1161/01.res.81.5.797

Cited by 190 publications

(149 citation statements)

References 48 publications

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“…Interestingly, NF-〉 binding to its target sequence was also shown to increase in hypertension, 32 and recent studies suggest that in vitro stretching may activate NF-〉 in cultured endothelial and smooth muscle cells. 33 In resting cells, NF-B is bound in the cytoplasm by its redox-sensitive inhibitor, IB, which masks the nuclear localization sequence on the transcription factor. We and others 25 showed that high pressure elicits rapid degradation of IB␣ 25 ( Figure 4B), which is likely responsible for the pressure-induced nuclear translocation of NF-〉.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

et al. 2005

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Background-Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-␤ superfamily member cytokine, plays an important role both in vascular development and pathophysiological processes, including endothelial activation that is likely to contribute to the development of coronary atherosclerosis, yet the factors that regulate arterial expression of BMP-2 are completely unknown. We tested the hypothesis that BMP-2 expression in endothelial cells is governed by an H 2 O 2 and nuclear factor (NF)-〉-dependent pathway that can be activated by both proinflammatory and mechanical stimuli. Methods and Results-The proinflammatory cytokine tumor necrosis factor (TNF)-␣ induced NF-〉 activation and elicited significant increases in BMP-2 mRNA and protein in primary coronary arterial endothelial cells and human umbilical vein endothelial cells that were prevented by NF-〉 inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H 2 O 2 also elicited NF-〉 activation and BMP-2 induction. In organ culture, exposure of rat arteries to high pressure (160 mm Hg) elicited H 2 O 2 production, nuclear translocation of NF-〉, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-␣, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF-␣ knockout mice. Key Words: free radicals Ⅲ cytokines Ⅲ growth factors T he transforming growth factor superfamily member cytokine, bone morphogenetic protein-2 (BMP-2), was originally detected in cartilage and bone 1 ; however, recent studies from this and other laboratories demonstrated that vascular endothelial and smooth muscle cells are also a significant source of BMPs. [2][3][4][5][6] First genetic analysis of patients with primary pulmonary hypertension indicated that a vascular BMP-2/BMP receptor system plays an important role in vascular physiology. 7,8 Indeed, BMP-2 has been shown to regulate a host of cellular functions, 2,4,5,9 including cardiovascular development, 9 neovascularization in tumors, 10 and smooth muscle cell chemotaxis in response to vascular injury. 2 Both BMP-2 (unpublished observation, 2004) and BMP-4, which are closely related by their amino acid sequence and act on the same receptor, 4,6 were shown to exert proinflammatory effects by inducing expression of adhesion molecules and enhancing monocyte adhesion. Endotheliumderived BMPs are also osteoinductive, 5 and hypotheses have been put forward that they may also contribute to vascular calcification during the development of atherosclerotic plaques. 3,5,11 Importantly, recent studies confirmed a striking upregulation of BMP-2/4 in atherosclerotic lesions. [2][3][4] Despite the growing evidence for the physiological/pathophysiological importance of BMP-2 in blood vessels, the mechanisms regulating endothelial BMP-2 expression have not yet been elucidated. Previously, we 12 have demonstrated that in coronary arteries in hyperhomocysteinemia, vascular i...

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Section: Discussionmentioning

confidence: 99%

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

et al. 2005

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“…17 Cells were then exposed to cyclic strain; medium was collected at 0, 20, 40, and 60 minutes; and absorbance was read (550 nm). Equivalent superoxide (O 2 Ϫ ) production was estimated by converting the optical density difference between samples with or without superoxide dismutase by using the molar extinction coefficient for cytochrome c:…”

Section: O 2 ؊ Productionmentioning

confidence: 99%

“…HASMCs were pretreated (1 hour) with N-acetyl-L-cysteine (NAC, 1 to 20 mmol/L; antioxidant), pyrrolidine dithiocarbamate (PDTC, 50 mol/L; antioxidant), 17 diphenyleneiodonium chloride (DPI, 1 to 20 mol/L; NADPH oxidase inhibitor), 18 indomethacin (10 mol/L, cyclooxygenase inhibitor), oxypurinol (10 mol/L, xanthine oxidase inhibitor), 17,18 N G -methyl-L-arginine (L-NMMA, 1 mmol/L; NO synthase inhibitor), staurosporine (1 to 20 nmol/L, nonspecific protein kinase inhibitor), Ro 31-8220 (0.1 mol/L, PKC inhibitor), 19 herbimycin A (2.0 mol/L, tyrosine kinase inhibitor), or PD 098,059 (50 mol/L, MAPK kinase inhibitor). 20 Cells were subjected to 20% strain in the presence of the same inhibitor for 12 hours.…”

Section: Ros No and Protein Kinase Inhibitorsmentioning

confidence: 99%

Cyclic Strain Increases Protease-Activated Receptor-1 Expression in Vascular Smooth Muscle Cells

et al. 2001

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Abstract-Cyclic strain regulates many vascular smooth muscle cell (VSMC) functions through changing gene expression.This study investigated the effects of cyclic strain on protease-activated receptor-1 (PAR-1) expression in VSMCs and the possible signaling pathways involved, on the basis of the hypothesis that cyclic strain would enhance PAR-1 expression, reflecting increased thrombin activity. Uniaxial cyclic strain (1 Hz, 20%) of cells cultured on elastic membranes induced a 2-fold increase in both PAR-1 mRNA and protein levels. Functional activity of PAR-1, as assessed by cell proliferation in response to thrombin, was also increased by cyclic strain. In addition, treatment of cells with antioxidants or an NADPH oxidase inhibitor blocked strain-induced PAR-1 expression. Preincubation of cells with protein kinase inhibitors (staurosporine or Ro 31-8220) enhanced strain-increased PAR-1 expression, whereas inhibitors of NO synthase, tyrosine kinase, and mitogen-activated protein kinases had no effect. Cyclic strain in the presence of basic fibroblast growth factor induced PAR-1 mRNA levels beyond the effect of cyclic strain alone, whereas no additive effect was observed between cyclic strain and platelet-derived growth factor-AB. Our findings that cyclic strain upregulates PAR-1 mRNA expression but that shear stress downregulates this gene in VSMCs provide an opportunity to elucidate signaling differences by which VSMCs respond to different mechanical forces. (Hypertension. 2001;38: 1038-1043.)

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“…Elevated blood pressure increases wall stress in a nonuniform distribution. 3,4 Increased wall stress has been proposed to be a proinflammatory stimulus, 5 as evidenced by the association between mechanical strain and the production of reactive oxygen species 6,7 and the expression of inflammatory gene products. 8 -10 Indeed, wall stress has been shown to be a biologically relevant stimulus for the development of atherosclerosis.…”

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confidence: 99%

Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice

2001

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Background-Angiotensin II may contribute to the development and progression of atherosclerotic lesions because of its growth and proinflammatory effects. We sought to determine whether angiotensin II-induced hypertension would augment and accelerate the development of atherosclerotic lesions in apoE-deficient mice. Methods and Results-Angiotensin II (0.7 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC) was administered to apoE-deficient mice via osmotic minipumps. The animals were placed on either standard chow or an atherogenic diet. After 8 weeks, the mean atherosclerotic lesion area in the descending thoracic and abdominal aortas of animals on a standard chow diet was 0.4Ϯ0.1% compared with 5.2Ϯ1.2% in those animals maintained on an atherogenic diet (PϽ0.0001). In angiotensin II-treated animals on standard chow, the mean lesion area was increased to 11.0Ϯ2.3%, which was further increased to 69.9Ϯ9.4% (PϽ0.0001) in angiotensin II-treated animals on an atherogenic diet. Similar findings were obtained when tissues from the ascending aorta were analyzed. At 8 weeks in mice receiving a standard chow diet, angiotensin II dramatically increased the atherosclerotic lesion area by 840Ϯ83 m 2 (PϽ0.0001). Animals on a high-fat diet had a similar marked increase in lesion area in response to angiotensin II (217Ϯ19 m 2 , PϽ0.0001). In contrast, when hypertension was induced with norepinephrine, only a modest effect on the atherosclerotic lesion area was observed. Conclusions-Angiotensin II-induced hypertension specifically increased the development of atherosclerosis in apoE knockout mice. This response was seen in animals receiving either standard chow or an atherogenic diet. These studies demonstrate the profound effect of angiotensin II on the development of atherosclerosis.

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Pulsatile Stretch Stimulates Superoxide Production and Activates Nuclear Factor-κB in Human Coronary Smooth Muscle

Cited by 190 publications

References 48 publications

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

Cyclic Strain Increases Protease-Activated Receptor-1 Expression in Vascular Smooth Muscle Cells

Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice

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