The existence of a local 5‐hydroxytryptaminergic system in peripheral arteries

Ni, Wei; Geddes, Timothy J.; Priestley, Jessica; Szasz, Theodora; Kuhn, Donald M.; Watts, Stephanie W.

doi:10.1038/bjp.2008.111

Cited by 63 publications

(67 citation statements)

References 28 publications

(41 reference statements)

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“…The TPH-2 isoform expression is restricted to neural cells and is a ratelimiting enzyme for serotonin biosynthesis (26)(27)(28). TPH-1 has been reported to be expressed in vascular cells (29). However, little is known about its expression and metabolism in fibroblasts and cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Cheng¹,

Kuo²,

Yan³

et al. 2012

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

118

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Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.tumor suppression | tryptophan metabolism | inflammation control C yclooxygenase-2 (COX-2) is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities. It is involved in multiple physiological functions and triggers key pathological processes, such as tumorigenesis and inflammation (1, 2). COX-2 is constitutively overexpressed in a wide variety of human cancers and is enhanced by proinflammatory stimuli (3, 4). There is convincing evidence for a causal role of COX-2 in tumorigenesis. Inhibition of COX-2 activities was reported to control human colorectal cancer (5-8). COX-2 induces tumorigenesis by promoting important cellular functions including cell proliferation, migration, and resistance to apoptosis (9-11). The induced COX-2 expression by proinflammatory and mitogenic factors in normal cells is tightly controlled (12) whereas its overexpression in cancer cells is attributed to dysregulated transcription (13). The endogenous control mechanisms for COX-2 expression in normal cells and the mechanisms underlying the dysregulation in cancer cells are poorly understood. We previously identified in the conditioned medium of human fibroblasts small molecules (named cytoguardins) that suppress COX-2 expression induced by proinflammatory mediators (14). NMR analysis of a semipurified fraction revealed compounds with indole moieties (14). However, the exact chemical structures remain elusive. In this study, we elucidated the structure of cytoguardins by comparing the metabolomic profiles between normal and cancer cells. ResultsCytoguardins Inhibit Cancer Cell COX-2. To determine that fibroblast factors are capable of suppressing cancer cell COX-2 expression, we cocultured human Hs68 foreskin fibroblasts (HsFb) with A549 lung cancer cells in a Boyden chamber for 24 h. A549 cells were removed and treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and COX-2 proteins were analyzed. HsFb suppressed A549 ...

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Section: Resultsmentioning

confidence: 99%

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Cheng¹,

Kuo²,

Yan³

et al. 2012

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

118

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“…The action of serotonin is mainly paracrine and involves a complex action through its transporter and different receptors (4). In the periphery, although the main site of serotonin synthesis is the enterochromaffin cells of the gut, TPH 1 expression and local serotonin synthesis have been shown to have a functional role in the cardiovascular system (12), mammary gland (13), and pancreas (14).…”

Section: Tphmentioning

confidence: 99%

Decreased osteoclastogenesis in serotonin-deficient mice

Chabbi-Achengli

Coudert

Crinon

et al. 2012

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

110

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Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH 1 ), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling. We therefore decided to investigate in detail bone remodeling in growing and mature TPH 1 knockout mice (TPH 1 −/−). Bone resorption in TPH 1 −/− mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH 1 −/− mice is cell-autonomous. Cultures from TPH 1 −/− in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH 1 and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.neuromediator | osteopetrosis B one remodeling is a highly integrated process that continuously renews mineralized tissue throughout the skeleton to assure harmonious growth, maintenance, and repair throughout the lifespan of the individual. It couples the resorption of mineralized bone by osteoclasts and bone formation by osteoblasts. Osteoblasts originate from mesenchymal stem cells (1), and osteoclasts are multinucleated cells derived from a hematopoietic precursor of the monocyte macrophage lineage (2). Dysregulation of osteoclast function or differentiation results in an osteopetrotic phenotype, with a marked increase in bone density. In contrast, increased bone resorption is associated with bone loss in diseases such as osteoporosis, arthritis, and metastatic bone lesions. Molecular communication between osteoblasts and osteoclasts is required to regulate the commitment, proliferation, and differentiation of bone cell precursors. The main osteoclastogenic signals are the receptor activator for NF-KB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), both of which are cytokines secreted by osteoblasts (3).Serotonin, or 5-hydroxytryptamine (5-HT), mediates a wide range of central functions, such as mood, behavior, sleep, blood pressure, and thermoregulation (4). Peripherally, serotonin is involved mainly in the regulation of vascular and heart functions (5, 6) and in gastrointestinal mobility (7). The diverse actions of 5-HT result from the presence of multiple 5-HT receptors (5-HTRs). These various different receptors have been divided into seven classes (5-HT 1 R to 5-HT 7 R) (8). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. There are two isoforms of this enzyme: TPH 2 is mainly expressed in brain, and...

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“…3). Peripheral arteries, which included the aorta and superior mesenteric artery, can synthesize 5-HT, take up 5-HT, metabolize 5-HT, release 5-HT, and bind 5-HT intracellularly (22)(23)(24). Perhaps the most intriguing finding was that arteries could make their own 5-HT.…”

Section: Where Does the 5-ht Come From?mentioning

confidence: 99%

The love of a lifetime: 5-HT in the cardiovascular system

Watts¹

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Serotonin [5-hydroxytryptamine (5-HT)] is an amine made from the essential amino acid tryptophan. 5-HT serves numerous functions in the body, including mood, satiety, and gastrointestinal function. Less understood is the role 5-HT plays in the cardiovascular system, although 5-HT receptors have been localized to every important cardiovascular organ and 5-HT-induced changes in physiological function attributed to activation of these receptors. This manuscript relates a few scientific stories that test the idea that 5-HT is important to the control of normal vascular tone, more so in the hypertensive condition. Currently, our laboratory is faced with two different lines of experimentation from which one could draw vastly different conclusions as to the ability of 5-HT to modify endogenous vascular tone and blood pressure. Studies point to 5-HT being important in maintaining high blood pressure, but other studies solidly support the ability of 5-HT to reduce elevated blood pressure. This work underscores that our knowledge of the functions of 5-HT in the cardiovascular system is significantly incomplete. As such, this field is an exciting one in which to be, because there are superb questions to be asked.

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The existence of a local 5‐hydroxytryptaminergic system in peripheral arteries

Cited by 63 publications

References 28 publications

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Decreased osteoclastogenesis in serotonin-deficient mice

The love of a lifetime: 5-HT in the cardiovascular system

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