Activation of the nucleus nuclear factor erythroid 2-related factor 2 via ghrelin/growth hormone secretagogue receptor 1a signaling by Yueju pill (越鞠丸) confers cardioprotective and antidepressant effects

OBJECTIVE: To investigate the efficacy and mechanistic foundations of the Traditional Chinese Medicine Yueju pill (YJP, 越鞠丸) for treating the complex comorbidity of heart failure and depression. METHODS: C57BL/6 male mice were used to establish a robust congestive heart failure (CHF) model with concomitant depressive manifestations. Echocardiographic assessments were conducted to evaluate cardiac structure and function in the mice. Depression-related behavioral tests and the detection of monoamine neurotransmitters were performed to assess the antidepressant-like effectiveness of YJP. Western blot analysis was conducted to measure the expression levels of key components in the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO1) antioxidant pathway, NRF2/brain-derived neurotrophic factor (BDNF) pathway, and ghrelin/growth hormone secretagogue receptor (GHS-R)1a pathway in the myocardium and hippocampus. To explore the mechanistic role of the ghrelin/GHS-R1a pathway, the ghrelin receptor antagonist D-Lys3-growth hormone-releasing peptide-6 was introduced to enable the iterative evaluation of the aforementioned parameters. RESULTS: YJP improved cardiac dysfunction and myocardial fibrosis and markedly ameliorated depressive behaviors. It also improved neuron damage, boosted the growth of dendritic spines to enhance synaptic plasticity, and alleviated monoamine neurotransmitter imbalances. Additionally, the NRF2/BDNF, ghrelin/GHS-R1a, and NRF2/HO1 antioxidant pathways were promoted by YJP, with the increased expression of key components of the three pathways. The addition of a GHS-R1a antagonist impaired the antidepressant and cardioprotective effects of YJP. CONCLUSIONS: YJP effectively improved cardiac dysfunction and depressive-like behaviors in mice by activating NRF2 viamediation of the ghrelin/GHS-R1a signaling axis within both the myocardial and hippocampal domains.