Catalytic consumption of nitric oxide by 12/15- lipoxygenase: Inhibition of monocyte soluble guanylate cyclase activation

Coffey, Marcus J.; Natarajan, Rama; Chumley, Philip H.; Coles, Barry A.; Thimmalapura, Pushpa-Rekha; Nowell, Mari Ann; Kühn, Hartmut; Lewis, Malcolm J.; Freeman, Bruce Α.; O'Donnell, Valerie Bridget

doi:10.1073/pnas.141136098

Cited by 67 publications

(43 citation statements)

References 62 publications

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“…We have also recently shown that these 12-LO-overexpressing cells (m12-LO cells) have a greater rate of nitric oxide consumption than the control cells (pcDNA cells). This suggests that LOs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as a catalytic sink for nitric oxide in the vasculature (40). These studies provide additional support for the important role of vascular and mononuclear 12-LO in vascular disorders.…”

Section: Discussionmentioning

confidence: 67%

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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126

137

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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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Section: Discussionmentioning

confidence: 67%

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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126

137

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“…Overall this would suggest different pathways for NO consumption. It has been shown for example that 15-lipoxygenase, prostaglandin-H synthase, and myeloperoxidase all consume NO to yield nitrite, and it is possible that these pathways may prevail under specific conditions (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, NO inactivation in non-striated tissues is poorly understood, and examination of NO consumption in various cells suggests mechanisms that differ in NO saturation, oxygen and cyanide sensitivity, and product formation (5)(6)(7)(8). Specific pathways include increased partition of NO in cell membranes (7) and consumption of NO by cytochrome c oxidase (9 -11), NADPH oxidase (12), 15-lipoxygenase (13), prostaglandin-H synthase (14), and myeloperoxidase (15).…”

Section: Nitric Oxide (No)mentioning

confidence: 99%

Cytoglobin Is Expressed in the Vasculature and Regulates Cell Respiration and Proliferation via Nitric Oxide Dioxygenation

Halligan

Jourd’heuil

2009

Journal of Biological Chemistry

108

121

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Disposition of the second messenger nitric oxide (NO) in mammalian tissues occurs through multiple pathways including dioxygenation by erythrocyte hemoglobin and red muscle myoglobin. Metabolism by a putative NO dioxygenase activity in non-striated tissues has also been postulated, but the exact nature of this activity is unknown. In the present study, we tested the hypothesis that cytoglobin, a newly discovered hexacoordinated globin, participates in cell-mediated NO consumption. Stable expression of small hairpin RNA targeting cytoglobin in fibroblasts resulted in decreased NO consumption and intracellular nitrate production. These cells were more sensitive to NO-induced inhibition of cell respiration and proliferation, which could be restored by re-expression of human cytoglobin. We also demonstrated cytoglobin expression in adventitial fibroblasts as well as vascular smooth muscle cells from various species including human and found that cytoglobin was expressed in the adventitia and media of intact rat aorta. These results indicate that cytoglobin contributes to cell-mediated NO dioxygenation and represents an important NO sink in the vascular wall. Nitric oxide (NO)2 plays a central role in the vasculature and regulates oxygen supply by relaxing smooth muscle and inhibiting mitochondrial respiration. NO is produced by nitric-oxide synthase and through mobilization of storage pools such as nitrite. Less is known on the mechanism of NO inactivation and removal in the vasculature, although it would be surprising that blood vessels rely on nonspecific chemical reactions to control its disposition.Blood removes NO through reaction with excess oxyhemoglobin in erythrocytes, but diffusional barriers such as the red blood cell-free layer near the vessel wall allow autocrine NO to occur in significant amounts in the vascular wall (1, 2). In striated muscles, oxymyoglobin is an NO scavenger, and studies using transgenic mice lacking myoglobin have demonstrated a role for oxymyoglobin in attenuating NO-mediated cardiac dysfunction (3, 4). In contrast, NO inactivation in non-striated tissues is poorly understood, and examination of NO consumption in various cells suggests mechanisms that differ in NO saturation, oxygen and cyanide sensitivity, and product formation (5-8). Specific pathways include increased partition of NO in cell membranes (7) and consumption of NO by cytochrome c oxidase (9 -11), NADPH oxidase (12), 15-lipoxygenase (13), prostaglandin-H synthase (14), and myeloperoxidase (15).Many of the above mechanisms implicate metalloproteins as modulators of NO bioavailability among which the role of oxyglobins such as oxyhemoglobin and oxymyoglobin have been already highlighted (16). One of the primary mechanisms is the dioxygenation of NO to form nitrate and the ferric (Fe(III)) form of the protein. The recent discovery of two new mammalian globins, cytoglobin and neuroglobin, would suggest that the reactions of NO with globins are not limited to red blood cells and striated muscles but could extend to other ...

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“…44 Our present observations of reduced growth and matrix responses in VSMC from LOKO mice suggest that these could be additional mechanisms for the atheroprotective role conferred by ablation of 12/15-LO. Since LO activation can lead to the consumption of nitric oxide, 45 this could be another key route by which vascular LO mediates the pathogenesis of atherosclerosis and hypertension. Patricia et al 46 showed that 12(S)-HETE treatment of endothelial cells could lead to increased monocyte binding and that the 12/15-LO ribozyme blocked high glucoseinduced binding of monocytes to endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase–Deficient Mice

et al. 2003

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Abstract-Biochemical and genetic evidence support the involvement of leukocyte-type 12/15-lipoxygenase enzyme and its products in the atherogenic process. We recently showed that products of the 12/15-lipoxygenase pathway play an important role in mediating hypertrophy, matrix protein production, and inflammatory gene expression in vascular smooth muscle cells (VSMC) through activation of mitogen activated protein kinases and key transcription factors. The current study is aimed at establishing the in vivo role of 12/15-lipoxygenase in VSMC by comparing growth factor-induced responses in VSMC derived from 12/15-lipoxygenase knockout mice versus genetic control wild-type mice. In the lipoxygenase knockout cells, 12/15-lipoxygenase protein was not expressed, and levels of its product, 12(S)-hydroxyeicosatetraenoic acid, were reduced (51% of wild type). Knockout cells exhibited significantly lower rates of growth factor-induced migration, fibronectin production, and incorporation of 3 H-thymidine and 3 H-leucine (54%, 55%, 61%, and 57% of wild type, respectively). Growth factor-induced superoxide production and p38 mitogen-activated protein kinase activation were also reduced in knockout cells. Serum-stimulated AP-1 transcription factor activation was markedly reduced (50% of wild type), whereas cAMP response element binding protein activation was abrogated in knockout cells. Furthermore, growth factor-induced mRNA expression of immediate early genes and fibronectin were also greatly reduced. These results suggest that the modulation of specific signaling pathways and growth-responsive genes may be responsible for the altered growth factor responses in the lipoxygenase knockout cells. Leukocyte-type 12-LO has a wide tissue distribution, including vascular smooth muscle cells (VSMC). 6,7 In mice, both leukocyte 12/15-LO and platelet 12-LO are expressed. 8 Studies indicate that LO inhibition reduced blood pressure in renovascular hypertensive rats. 9 Furthermore, 12(S)-HETE levels were elevated in spontaneously hypertensive rats compared with age-matched Wistar-Kyoto rats, and 12(S)-HETE directly regulated calcium signals in VSMC. 10,11 Several lines of evidence implicate 12/15-LO in the development of atherosclerosis. 12/15-LO can mediate the oxidation of LDL, 12 and the enzyme and its products have been detected in atherosclerotic lesions. 13,14 Convincing evidence comes from recent data showing that disruption of 12/15-LO in apoE Ϫ/Ϫ or LDL-R Ϫ/Ϫ mice significantly reduced atherosclerosis in these mice models. 15,16 Additionally, growth factors (GFs) such as angiotensin II (Ang II) and platelet-derived growth factor (PDGF) and cytokines such as IL-1, IL-4, and IL-8 could induce 12/15-LO activity and expression in VSMC. 7,[17][18][19] Furthermore, the 12-LO product 12(S)-HETE could induce VSMC migration and extracellular matrix production. 20,21 Ang II-induced hypertrophy as well as PDGF-induced chemotactic effects were significantly blocked by pharmacological LO inhibitors and a molecular inhibitor, 12-LO ribozyme...

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Catalytic consumption of nitric oxide by 12/15- lipoxygenase: Inhibition of monocyte soluble guanylate cyclase activation

Abstract: 12͞15-Lipoxygenase (LOX) activity is elevated in vascular diseasesarachidonate ͉ linoleate ͉ hypertension ͉ atherosclerosis

Cited by 67 publications

References 62 publications

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

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

Cytoglobin Is Expressed in the Vasculature and Regulates Cell Respiration and Proliferation via Nitric Oxide Dioxygenation

Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase–Deficient Mice

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