Beneficial effects of aryl hydrocarbon receptor activation on post-infarction myocardial metabolism, inflammation and fibrosis: implications from multi-omics

Background

Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1′H-indole-3′‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the aryl hydrocarbon receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear.

Methods

The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways.

Results

ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while hexokinase inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis.

Conclusion

The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.