A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury

Ho, Yen‐Chun; Wu, M. K.; Su, Chen-Hsuan; Chen, Chung-Huang; Ho, Hua-Hui; Lee, Guan-Lin; Lin, Wei‐Shiang; Lin, Wea‐Lung; Hsu, Yu‐Juei; Kuo, Cheng-Chin; Wu, Kenneth K.; Yet, Shaw‐Fang

doi:10.1038/srep25374

Cited by 31 publications

(27 citation statements)

References 49 publications

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“…1) derived from endothelium inhibits LPS-induced endothelial leakage and suppresses the overexpression of proinflammatory mediators (cyclooxgenase-2 and interleukin-6) regulated by LPS- or cecal ligation and puncture [95]. Furthermore, 5-MTP treatment protects against ligation injury-induced endothelial loss and detachment, decreases endothelial expression of intercellular adhesion molecular-1 (ICAM-1) and VCAM-1, suggesting attenuation of endothelial dysfunction [96]. …”

Section: Role Of Dysregulated Kp In Cvdmentioning

confidence: 99%

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Song

Ramprasath

Wang

et al. 2017

Cell. Mol. Life Sci.

181

134

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Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine aminotransferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP-enzyme inhibitors against CVD is briefly discussed.

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Section: Role Of Dysregulated Kp In Cvdmentioning

confidence: 99%

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Song

Ramprasath

Wang

et al. 2017

Cell. Mol. Life Sci.

181

134

View full text Add to dashboard Cite

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“…It was reported in murine models that following mechanical or ischemic injury, ECs are damaged and detached resulting in denudation [ 20 – 23 ]. In response to injury, vascular SMCs migrate to intimal layer and proliferate.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, they release pro-inflammatory cytokines and collagen, resulting in intimal hyperplasia [ 20 , 21 ]. 5-MTP administration to the murine vascular injury models results in attenuation of denudation and intimal hyperplasia [ 22 , 23 ]. 5-MTP reduces endothelial loss by two possible mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) accumulation at the intimal region play an important role in intimal hyperplasia [ 27 – 29 ]. 5-MTP selectively inhibits cytokine-induced SMC migration and proliferation without an effect on VEGF-induced SMC migration and proliferation [ 23 ]. Expression of vascular SMC contractile proteins depends on binding of serum response factor (SRF) and its co-factor myocardin-related transcription factor-A (MRTF-A) to the promoter region of SMC marker genes, such as SM-α actin [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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5-methoxytryptophan: an arsenal against vascular injury and inflammation

Kuo

Yet

et al. 2020

J Biomed Sci

Self Cite

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5-methoxytryptophan (5-MTP) is an endothelial factor with anti-inflammatory properties. It is synthesized from L-tryptophan via two enzymatic steps: tryptophan hydroxylase-1 (TPH-1) and hydroxyindole O-methyltransferase. Lipopolysaccharide (LPS) and pro-inflammatory cytokines suppress endothelial 5-MTP production by inhibiting TPH-1 expression. 5-MTP protects endothelial barrier function and promotes endothelial repair, while it blocks vascular smooth muscle cell migration and proliferation by inhibiting p38 MAPK activation. 5-MTP controls macrophage transmigration and activation by inhibiting p38 MAPK and NF-κB activation. 5-MTP administration attenuates arterial intimal hyperplasia, defends against systemic inflammation and prevents renal fibrosis in relevant murine models. Serum 5-MTP level is depressed in human sepsis as well as in mice with sepsis-like disorder. It is reduced in chronic kidney disease and acute myocardial infarction in humans. The reported data suggest that serum 5-MTP may be a theranostic biomarker. In summary, 5-MTP represents a new class of tryptophan metabolite which defends against inflammation and inflammation-mediated tissue damage and fibrosis. It may be a valuable lead compound for developing new drugs to treat complex human inflammatory disorders.

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“…22 Various 5-methoxyindoles-a novel class of endothelial protective molecules-including 5-methoxytryptophan protect endothelial function and defend against inflammatory diseases, including systemic inflammation, vascular injury, and cancer. [23][24][25] In our present study, we examined the effects of 5-MTP on PM-induced pulmonary inflammation, pulmonary vascular alteration, and OPN concentrations in BALF after exposure for 4 weeks.…”

mentioning

confidence: 99%

Persistent elevation of blood pressure by ambient coarse particulate matter after recovery from pulmonary inflammation in mice

Tsai

Chen

et al. 2019

Environmental Toxicology

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Exposure to ambient particulate matter (PM) is associated with hypertension and cardiovascular diseases. Recently, we reported that exposure to fine and coarse PM caused pulmonary inflammation and pulmonary small arterial remodeling in mice, and osteopontin (OPN) level was elevated following PM exposure. However, in the present study, cotreatment with 5‐methoxytryptophan for 4 weeks partially reduced coarse PM‐induced pulmonary inflammation without reducing pulmonary OPN secretion or recovery from pulmonary arterial remodeling in mice. Persistent vascular dysfunction may lead to vascular remodeling. Therefore, we further compared the relationship between coarse PM‐induced inflammation and vascular dysfunction by exposing mice to PM before and after cessation of PM exposure. Oropharyngeal aspiration of PM for 8 weeks induced pulmonary inflammation and pulmonary small artery remodeling in mice, as well as increased serum C‐reactive protein and OPN concentrations and systolic blood pressure (SBP). After the cessation of PM exposure for another 8 weeks, lung inflammation had recovered and vascular remodeling had partially recovered. Elevation of OPN, metalloproteinases (MMPs), and cytokines in bronchioalveolar lavage were significantly reduced. However, PM‐induced systemic responses did not recover after the cessation of PM exposure. Notably, not only serum OPN and SBP remained significantly elevated; also, serum endothelin‐1, MMP‐9, and keratinocyte‐derived chemokine concentrations were significantly increased after cessation of PM exposure for another 8 weeks. These data suggested that systemic inflammation and systemic vascular dysfunction might be important in PM‐induced elevation of SBP. Furthermore, SBP elevation was persistent after cessation of PM exposure for 8 weeks.

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A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury

Cited by 31 publications

References 49 publications

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

5-methoxytryptophan: an arsenal against vascular injury and inflammation

Persistent elevation of blood pressure by ambient coarse particulate matter after recovery from pulmonary inflammation in mice

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