Integrated analysis reveals neuro-immune pathway in the central nervous system that supports SGLT2i’s protective effects in treatment of cardiac remodeling
Abstract
Background: Despite growing evidence of sodium-dependent glucose transporters 2 inhibitors (SGLT2i) improving heart failure, their mechanisms remain unclear. This study explored the effects of empagliflozin (EM) on sympathetic nerve activity and potential neuroimmune pathways.
Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed in hypothalamic tissue of a DOCA-salt mouse model to screen for cellular changes. Validation of relevant mechanisms in DOCA-salt and high-salt diet (HSD) mouse models. Additionally, clinical data from 1,189 hospitalized heart failure patients were analyzed to evaluate the translational relevance of the experimental findings.
Results: EM treatment was associated with protective effects against cardiac remodeling in both DOCA-salt and HSD mice. Both models exhibited sympatho-excitation and neuronal hyperactivity in pre-autonomic brain regions, which appeared to be blunted by EM co-treatment. snRNA-seq analysis suggested that cellular interplay among vascular cells, microglia, and inhibitory neurons might be involved in these processes. Specifically, high-salt intake was linked to peripheral immune activation, including lymphocytosis and elevated plasma interferon-γ, which potentially mediated microglial state transitions. EM might counteract the disease-associated upregulation of protein ubiquitination. Clinically, SGLT2i use was significantly associated with reduced lymphocyte counts in specific patient subgroups.
Conclusions:…
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