Ergothioneine attenuates cardiac fibrosis induced by a high-fat diet in spontaneously hypertensive rats.

Ergothioneine (ERG) is a dietary thiol that is selectively accumulated in mammalian tissues via a specific transporter and may protect the cells against oxidative and inflammatory burden. In this study, we investigated the protective effects of ERG on high-fat diet (HFD)-induced cardiac fibrosis in the spontaneously hypertensive rats (SHR). ERG treatment (50 mg/kg daily, for 10 weeks) attenuated cardiac remodeling, as evidenced by reduced levels of the fibrosis markers hydroxyproline, α-smooth muscle actin, and galectin-3 increased by HFD. HFD induced obesity and altered plasma concentrations of metabolic hormones (thyroxine, leptin, and FGF21) and these changes were not affected by ERG. ERG suppressed SMAD-2 expression, indicating inhibition of TGFβ-driven profibrotic signaling, and favorably modulated extracellular matrix composition by reducing the collagen I content as well as the collagen I/collagen III ratio. In parallel, ERG enhanced antioxidant defense, as shown by upregulated expression of Sod2, which encodes mitochondrial superoxide dismutase, and reduced expression of the profibrotic Nox4, thereby demonstrating protective actions in the heart. ERG supplementation prevented the HFD-induced increase in the neutrophil-to-lymphocyte ratio, which is a biomarker of the stress response and immune burden. In summary, ERG attenuated HFD-induced maladaptive cardiac remodeling in SHR rats by modulating extracellular matrix composition and reducing fibrosis markers, likely by mitigating the pro-oxidative state. These findings suggest that ERG supplementation could serve as an adjunctive strategy to prevent cardiovascular disease in individuals with hypertension who consume a Western-type diet.