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Tryptophan is an essential amino acid and an important source for protein synthesis, and its various metabolites exert diverse physiological functions. We have previously shown that one of the tryptophan metabolites, 5-methoxytryptophan (5-MTP), attenuates inflammatory cytokine-induced p38 MAPK activation and maintains vascular smooth muscle cells (VSMCs) in a differentiated phenotype, thereby protecting against intimal hyperplasia in mice. Hydroxyindole O-methyltransferase (HIOMT), the last enzyme for melatonin synthesis, has been shown to produce 5-MTP in non-pineal cells. Human HIOMT (hHIOMT) has 3 isoforms: 373, 345, and 298 amino acids. hHIOMT345 is the functional isoform for melatonin generation in pineal cells whereas the active isoform in fibroblasts is hHIOMT298 for 5-MTP production. It is unclear whether VSMCs express HIOMT nor is it known the HIOMT isoform catalyzes 5-MTP synthesis in VSMCs.

We show for the first time that hHIOMT373 is the active isoform responsible for 5-MTP synthesis in VSMCs. Compared with wild-type mice, hHIOMT373 transgenic mice had high levels of hHIOMT and enhanced 5-MTP expression in the medial layer of the arteries. Importantly, transgenic mice had smaller neointima after vessel injury. Intriguingly, tryptophan metabolite serotonin and its synthetic enzyme aromatic L-amino acid decarboxylase (AADC) were reduced in transgenic mouse arteries. In VSMCs, inflammatory cytokine IL-1b increased AADC and serotonin levels that could be mitigated by 5-MTP.

treatment or HIOMT overexpression via suppressing p38 MAPK pathway. Interestingly, serotonin promoted VSMC proliferation and decreased VSMC contractile marker levels through ERK1/2 activation, which could not be abrogated by 5- MTP administration or HIOMT overexpression. Taken together, we unveiled a previously unrecognized function of HIOMT in vascular disease. hHIOMT373 mediated its protection against injury-induced intimal hyperplasia via reprograming tryptophan metabolism by increasing 5-MTP and decreasing serotonin levels in VSMCs. Mechanistically, HIOMT-5- MTP suppressed AADCserotonin induction through inhibiting p38 MAPK activation whereas serotonin exerted opposing effects of 5-MTP in VSMCs via ERK1/2 pathway.