Key result
IDO1 deficiency and consequent kynurenine insufficiency protected against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.
Why the study?
Aberrant amino acid metabolism is implicated in cardiac hypertrophy, but the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive.
Does IDO1 deletion or kynurenine insufficiency prevent pathological cardiac hypertrophy in preclinical models?
Does IDO1 deletion or kynurenine insufficiency prevent pathological cardiac hypertrophy in preclinical models?
IDO1 deficiency and consequent kynurenine insufficiency protect against pathological cardiac hypertrophy via the AhR-GATA4 axis, identifying a potential therapeutic target for cardiac remodeling.
IDO1-Kyn pathway modulation attenuates hypertrophy in mice; leaves open therapeutic targeting in human cardiac remodeling.
BACKGROUND: Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy. METHODS: Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography-mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA. RESULTS: IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice's hearts using liquid chromatography-mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis. CONCLUSIONS: This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.
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Wang et al. (2023) studied Pathological cardiac hypertrophy. IDO1 deletion or inhibition vs. Wild-type or vehicle control was evaluated on Myocardial remodeling and heart function. IDO1 deficiency and consequent kynurenine insufficiency protected against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.
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