Increased Levels of 12(S)-HETE in Patients With Essential Hypertension

González-Núñez, Daniel; Clària, Joan; Rivera, Francisca; Poch, Esteban

doi:10.1161/01.hyp.37.2.334

Cited by 86 publications

(68 citation statements)

References 28 publications

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“…6A Inset). The production of 12-HETE after BK application was also confirmed by an enzyme immunoassay by using a polyclonal antibody specific to 12(S)-HETE (14). As shown in Fig.…”

Section: Resultsmentioning

confidence: 61%

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia

Shin

Cho

Hwang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

342

291

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The capsaicin-sensitive vanilloid receptor (VR1) was recently shown to play an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. We hypothesized that pain-producing inflammatory mediators activate capsaicin receptors by inducing the production of fatty acid agonists of VR1. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain. V R1, a cloned capsaicin receptor, is a nonspecific cation channel expressed preferentially in small sensory neurons and activated by the vanilloids, capsaicin and resiniferatoxin (1). Because VR1 is also activated by heat and acid (1, 2), it is now considered to be a molecular sensor that detects a variety of painful stimuli. Indeed, recent experiments performed in mice that lack VR1 demonstrated that the receptor is essential for inflammation-induced heat hyperalgesia (3, 4). Therefore, understanding the cellular mechanisms by which capsaicin receptors are activated by inflammatory mediators may be a key to identifying novel therapeutic targets for pain treatment. Because of the presence of VR1 in sensory neurons and an apparent role in inflammatory hyperalgesia, endogenous activators of VR1 have been suspected. We recently demonstrated that products of the lipoxygenase pathway of arachidonic acid (AA) metabolism can activate capsaicin receptors (5). Among the eicosanoids tested, the 12-lipoxygenase product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), structurally similar to capsaicin, was the most potent VR1 agonist. Thus, metabolic products of lipoxygenases become candidates for the endogenous capsaicinlike substances. However, the upstream signals that stimulate lipoxygenase and activate VR1 are elusive.Bradykinin (BK) is a potent inflammatory mediator that causes pain and hyperalgesia. BK is known to activate as well as sensitize sensory neurons to other stimuli. Various signaling pathways have been suggested to mediate the sensitizing effect of BK on sensory neurons (6, 7). However, activation mechanism by BK is not known. BK is now known to stimulate the production of AA in sensory neurons (8), a key substrate of lipoxygenases. Therefore, on the basis of previous observations that products of lipoxygenase activate VR1 (5), we hypothesized that BK excites sensory neurons by opening the capsaicin receptor via production of 12-lipoxygenase products of AA metabolism. Materials and MethodsCell Culture. Experiments were carried out according to the Ethical Guidelines of the International Association for the Study of Pain and approved by the research ethics committee for the use of animals of the Seoul National University and the University of California, San Francisco. Thoracic and lumbar dorsal root ganglia (DRGs) were dissected from 1-to 2 day-...

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“…6A Inset). The production of 12-HETE after BK application was also confirmed by an enzyme immunoassay by using a polyclonal antibody specific to 12(S)-HETE (14). As shown in Fig.…”

Section: Resultsmentioning

confidence: 61%

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia

Shin

Cho

Hwang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

342

291

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“…As previously shown, Ang II increases 12-LO expression (Natarajan et al, 1993;Kim et al, 1995). The activities of 12-LO and the 12-LO metabolite 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) are increased in SHR, and many studies have demonstrated a role for 12-LO and 12(S)-HETE in the pathogenesis of experimental and Ang II-induced hypertension (Sasaki et al, 1997;González-Núnez et al, 2001) and in cytokine-induced VSMCs migration and proliferation (Natarajan et al, 1997). In the present study, we demonstrated the inhibitory action of CCL5 on Ang II-induced 12-LO mRNA expression and production via AT2 receptor in SHR VSMCs.…”

Section: Discussionmentioning

confidence: 92%

Downregulation of Angiotensin II-Induced 12-Lipoxygenase Expression and Cell Proliferation in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats by CCL5

Kim

2009

Korean J Physiol Pharmacol

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“…Increased levels of 12(S)-HETE have been observed in hypertensive and diabetic patients (50,51). The LO pathway has been implicated in the oxidation of low density lipoprotein to its atherogenic form and in the pathogenesis of atherosclerosis (52)(53)(54).…”

Section: Discussionmentioning

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

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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Increased Levels of 12(S)-HETE in Patients With Essential Hypertension

Cited by 86 publications

References 28 publications

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia

Downregulation of Angiotensin II-Induced 12-Lipoxygenase Expression and Cell Proliferation in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats by CCL5

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

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