Crosstalk mechanism exploration of the medical food homology compound β-ecdysterone with sympathetic overactivation-induced cardiac hypertrophy

Medicine and food homological (MFH) products are known for their enhanced safety and tolerability, minimizing significant side effects and making them ideal for prolonged use in cardiovascular diseases. β-ecdysterone has been identified as a promising functional MFH ingredient derived from Achyranthes bidentata , showing potential against cardiovascular diseases in previous studies. This study aims to elucidate the neuroregulatory mechanisms of β-ecdysterone on cardiac hypertrophy. The anti-hypertrophic effects of β-ecdysterone were validated both in vivo and in vitro , and transcriptomic analysis of cardiac tissue revealed the involvement of neuroregulatory pathways. ELISA measurements of sympathetic neurotransmitter norepinephrine (NE) and parasympathetic neurotransmitter acetylcholine (Ach) showed that β-ecdysterone significantly reduced NE levels. Metabolomic analysis of neurotransmitters confirmed a decrease in NE metabolites, which was significantly correlated with hypertrophic phenotypic xparameters. Transcriptomic analysis of cardiovascular center medulla tissue identified that β-ecdysterone modulates signaling pathways associated with cardiac contraction and hypertrophy. Through Weighted Gene Co-Expression Network Analysis (WGCNA) of transcriptomic data from both the heart and medulla, and correlational analysis with hypertrophic markers, Dhx37 was identified as a key gene. Further analysis of Dhx37 gene expression in both heart and medulla tissues revealed that β-ecdysterone influences Dhx37 expression in cardiac tissue. Using a co-culture model of sympathetic neurons (PC-12 cells) and cardiomyocytes (H9C2 cells), β-ecdysterone was shown to reduce NE secretion and calcium channel activity in PC-12 cells under Angiotensin II (AngII) stimulation. Knockdown of Dhx37 in cardiomyocytes abrogated this effect, indicating that Dhx37 mediates β-ecdysterone’s regulation of sympathetic neuronal activity and neurotransmitter secretion in the context of cardiac hypertrophy. This study expands our understanding of the pharmacological effects of β-ecdysterone on cardiac hypertrophy, providing a novel potential target for the regulation of cardiac-sympathetic neuron interactions.