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Wireless, battery-free vagal electrical stimulation: A novel approach to inhibit cardiac hypertrophy via H3K18 lactylation mediated mitophagy

Year: 2025

Type: article

Abstract: Electrical stimulation (ES) has been established as a reliable and beneficial approach in therapeutic rehabilitation, exhibiting negligible side effects. Nevertheless, research focusing on the application of ES for cardiac hypertrophy remains limited, as it fails to provide an enduring remedy for chronic diseases. In this investigation, vagal ES, characterized by its wireless, battery-free, and fully implantable nature, was utilized to treat cardiac hypertrophy. The vagus nerve at the stimulation site was carefully embedded within an envelope, sealed securely using multiple bioabsorbable sutures. Subsequently, a cardiac hypertrophy model was induced in rats via abdominal aortic coarctation for four weeks. The findings of this investigation demonstrated that ES markedly attenuated cardiac hypertrophy. Metabolomic analysis revealed a notable reduction in lactate levels within myocardial tissue following ES. Proteomic analysis of myocardial tissues indicated a substantial decrease in the expression of autophagy and mitophagy-related proteins after ES. Additionally, ChIP-seq result revealed a specific binding interaction between H3K18 lactylation (H3K18la) and BCL2 interacting protein 3 (Bnip3), while luciferase reporter assays demonstrated that H3K18la directly governed Bnip3 transcriptional activation, exploring its role in modulating mitophagy. Mechanistically, it was shown that ES reduced lactate accumulation through the upregulation of monocarboxylate transporter 4 (MCT4) by decreasing norepinephrine (NE) levels. Furthermore, ES reversed cardiac hypertrophy by diminishing H3K18la levels, thus inhibiting Bnip3 protein expression. This pathway assists in diminishing cardiac hypertrophy, emphasizing the critical involvement of the afferent vagal pathway in regulating cardiac hypertrophy. Vagal electrical stimulation suppresses cardiac hypertrophy by reducing excessive mitophagy in cardiomyocytes. Vagal electrical stimulation decreases sympathetic innervation of the myocardium, releasing less norepinephrine, which increases the protein expression of MCT4 in cardiomyocytes. Upregulation of MCT4 reduces intracellular lactate overload and H3K18 lactylation, and then reduces excessive mitophagy, ultimately maintaining the basic function of mitochondria and inhibiting cardiac hypertrophy. • Wireless, battery-free vagal electrical stimulation system is used to treat cardiac hypertrophy. • Vagal electrical stimulation reduces the levels of H3K18la in cardiomyocytes of rats with cardiac hypertrophy. • Vagal electrical stimulation effectively inhibits autophagy and mitophagy in cardiomyocytes of rats exposed to AAC. • ChIP-seq results identifies Bnip3 as a binding partner for H3K18la, exploring its role in modulating mitophagy. • Vagal electrical stimulation attenuates mitophagy in cardiomyocytes by regulating the brain-heart axis.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2025.107760