Tryptophan metabolite 5-methoxytryptophan ameliorates arterial denudation-induced intimal hyperplasia via opposing effects on vascular endothelial and smooth muscle cells

Chen, Chung-Huang; Ho, Yen‐Chun; Ho, Hua-Hui; Liang, Liyu; Jiang, Wei-Cheng; Lee, Guan-Lin; Lee, Jen‐Kuang; Hsu, Yu‐Juei; Kuo, Cheng-Chin; Wu, Kenneth K.; Yet, Shaw‐Fang

doi:10.18632/aging.102350

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…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%

5-methoxytryptophan: an arsenal against vascular injury and inflammation

Kuo

Yet

et al. 2020

J Biomed Sci

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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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Section: Introductionmentioning

confidence: 99%

5-methoxytryptophan: an arsenal against vascular injury and inflammation

Kuo

Yet

et al. 2020

J Biomed Sci

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“…5-MTP was reported to be an arsenal against LPS- induced systemic inflammation by blocking p38 MAPK activation [ 60 ]. It protects vascular barrier function and endothelial integrity by inhibiting p38-mediated damage [ 61 , 87 , 88 ]. 5-MTP effectively prevents vascular intimal hyperplasia and vascular smooth muscle cell migration by blocking p38 MAPK activity [ 89 ].…”

Section: Melatonin and 5-mtp Target P38 Mapkmentioning

confidence: 99%

Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

2021

IJMS

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Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.

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“…5-MTP protects endothelial VE-cadherin and barrier functions by blocking p38 MAPK activation [ 6 ]. It inhibits LPS-induced macrophage activation and cytokine-induced vascular smooth muscle proliferation and migration via suppressing the p38 MAPK pathway [ 4 , 70 ]. p38 MAPK has been considered as a target for cancer treatment and several p38 MAPK inhibitors have been evaluated for their anti-cancer effects in clinical trials.…”

Section: 5-mtp Controls Cancer Cell Emt and Migration By Interrupting P38 Mapk Pathwaymentioning

confidence: 99%

Cytoguardin: A Tryptophan Metabolite against Cancer Growth and Metastasis

2021

IJMS

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Cytoguardin was identified in the conditioned medium of fibroblasts as a tryptophan metabolite, 5-methoxytryptophan (5-MTP). It is synthesized via two enzymatic steps: tryptophan hydroxylase (TPH) and hydroxyindole O-methyltransferase (HIOMT). A truncated HIOMT isoform, HIOMT298, catalyzes 5-MTP synthesis. Cancer cells produce scarce 5-MTP due to defective HIOMT298 expression. 5-MTP inhibits cancer cell COX-2 expression and thereby reduces COX-2-mediated cell proliferation and migration. 5-MTP also inhibits MMP-9 expression and thereby reduces cancer cell invasion. 5-MTP exerts its anti-cancer effect by blocking p38 MAPK and p38-mediated NF-κB and p300 HAT activation. The stable transfection of A549 cells with HIOMT298 restores 5-MTP production which renders cancer cells less aggressive. The implantation of HIOMT-transfected A549 into subcutaneous tissues of a murine xenograft tumor model shows that HIOMT-transduced A549 cells form smaller tumors and generate fewer metastatic lung nodules than control A549 cells. HIOMT298 transfection suppresses aromatic amino acid decarboxylase (AADC) expression and serotonin production. Serotonin is a cancer-promoting factor. By restoring 5-MTP and suppressing serotonin production, HIOMT298 overexpression converts cancer cells into less malignant phenotypes. The analysis of HIOMT expression in a human cancer tissue array showed reduced HIOMT levels in a majority of colorectal, pancreatic, and breast cancer. HIOMT298 may be a biomarker of human cancer progression. Furthermore, 5-MTP has the potential to be a lead compound in the development of new therapy for the chemoprevention of certain cancers such as hepatocellular cancer.

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Tryptophan metabolite 5-methoxytryptophan ameliorates arterial denudation-induced intimal hyperplasia via opposing effects on vascular endothelial and smooth muscle cells

Cited by 12 publications

References 38 publications

5-methoxytryptophan: an arsenal against vascular injury and inflammation

5-methoxytryptophan: an arsenal against vascular injury and inflammation

Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

Cytoguardin: A Tryptophan Metabolite against Cancer Growth and Metastasis

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