Integrated analysis reveals neuro-immune pathway in the central nervous system that supports SGLT2i`s protective effects in treatment of cardiac remodeling

BackgroundGrowing evidence are showing beneficial effects of sodium glucose transport protein 2 inhibitors (SGLT2i) in treatment of heart failure, but underlying neurogenic mechanism remains unclear. In this study the effect of empagliflozin (EM) on sympatho-excitation and potential neurogenic mechanism for EMs therapeutic effects on cardiac remodeling were studied. MethodsDeoxycorticosterone acetate (DOCA)-salt and high-salt (8%) diet (HSD) mouse models were utilized. Single-cell RNA sequencing was used to explore the mechanism by which SGLT2 inhibitors improve cardiac remodeling in hypertension. Meanwhile, blood samples were collected from hospitalized patients diagnosed with heart failure to verify the results of animal studies. ResultsIn DOCA-salt or HSD treated mice, EM was associated with a protective, blood pressure-independent effect on cardiac remodeling. Both DOCA-salt and HSD induced sympatho-excitation, together with neuronal hyper-activity in the pre-autonomic regions of brain, and these were blunted in mice with EM co-treatment. Additionally, single-nucleus RNA sequencing using hypothalami indicated that cellular interplays among the vessels, microglia and inhibitory neurons were involved in the disease- and EM-associated actions. Further analysis of microglia pinpointed a close involvement of peripheral immune activation in disease-associated state transformation of microglia, during DOCA-salt or HSD treatment, including increased lymphocytes count and plasma level of interferon-{gamma}. Differentially expressed genes in neurons highlighted that EM abolished disease-associated upregulation of protein ubiquitination, which might support imbalance of presympathetic excitatory/inhibitory tones, and vasopressin production. In patients blood samples, EM was associated with significant elevation of hematocrit value in all groups, and reduction of lymphocytes counts in the patients with high NT-proBNP value (> 2550 pg/mL, no diuretic co-treatment). ConclusionsOur data provide a neuro-immune pathway by which EM blunts disease-associated cardiac sympathetic tone and hypertrophic remodeling.