5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular disease is unknown. In this study, we investigated whether 5-MTP protects against vascular remodeling following arterial injury. Measurements of serum 5-MTP levels in healthy subjects and patients with coronary artery disease (CAD) showed that serum 5-MTP concentrations were inversely correlated with CAD. To test the role of 5-MTP in occlusive vascular disease, we subjected mice to a carotid artery ligation model of neointima formation and treated mice with vehicle or 5-MTP. Compared with vehicle-treated mice, 5-MTP significantly reduced intimal thickening by 40% 4 weeks after ligation. BrdU incorporation assays revealed that 5-MTP significantly reduced VSMC proliferation both in vivo and in vitro. Furthermore, 5-MTP reduced endothelial loss and detachment, ICAM-1 and VCAM-1 expressions, and inflammatory cell infiltration in the ligated arterial wall, suggesting attenuation of endothelial dysfunction. Signaling pathway analysis indicated that 5-MTP mediated its effects predominantly via suppressing p38 MAPK signaling in endothelial and VSMCs. Our data demonstrate a novel vascular protective function of 5-MTP against arterial injury-induced intimal hyperplasia. 5-MTP might be a therapeutic target for preventing and/or treating vascular remodeling.
Vascular smooth muscle cells (VSMCs) in the blood vessel wall exhibit a differentiated phenotype; their main function is contraction and to regulate vascular tone. In response to injury, VSMCs undergo a phenotypic transition whereby they proliferate and migrate from the medial layer into the intima, contributing to lesion formation and atherosclerosis. 5-methoxytryptophan (5-MTP), a recently identified novel tryptophan metabolite, has been shown to inhibit cancer cell growth, migration, and cancer metastasis. We hypothesized that 5-MTP might play an analogous role in vascular disease as in tumorigenesis. To test our hypothesis, we subjected 12 weeks old C57BL/6 mice to a carotid artery cessation of blood flow model to induce neointima formation. Following surgery, mice were treated with vehicle (PBS) or 100 mg/kg of 5-MTP by intraperitoneal injection 3 times a week. Four weeks later, carotid arteries were harvested for histological analysis. H&E and elastin staining revealed robust neointima in ligated carotids of vehicle-treated mice. In contrast, 5-MTP significantly attenuated neointima formation. Given that proinflammatory cytokine interleukin 1 beta (IL-1β) is increased in the injured vessel wall, we examined whether IL-1β affected VSMC phenotypic modulation. Indeed, IL-1β downregulated VSMC marker SM α-actin expression and increased VSMC proliferation and migration. Importantly, in VSMCs, 5-MTP attenuated IL-1β-mediated SM α-actin downregulation, proliferation, and migration, suggesting a potential role of 5-MTP in controlling VSMC phenotypic modulation. Furthermore, 5-MTP inhibited IL-1β-mediated p38 MAPK activation. Inhibiting p38 MAPK activation by SB203580 dose-dependently decreased IL-1β-induced VSMC proliferation. Taken together, our results suggest an important role of 5-MTP in vascular disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.