Upregulation of GABRB1 drives N-linked glycosylation of CDH2 to potentiate dilated cardiomyopathy

Background ? The brain – heart axis, a dynamic network integrating neural, mechanical, and biochemical pathways, is essential for cardiovascular homeostasis. Autonomic dysregulation is implicated in dilated cardiomyopathy (DCM), yet the molecular mechanisms linking neuromodulation to myocardial pathology remain poorly understood. The GABAergic system, a key inhibitory neuromodulatory network, regulates sympatho-vagal balance via ionotropic GABA-A receptors, including the β1 subunit (GABRB1). This study investigates the role and mechanistic basis of GABRB1 in DCM.

Methods: Multi-omic profiling—including single-cell RNA sequencing, ATAC-seq, and spatial transcriptomics—was performed on human left ventricular tissues from DCM patients and controls. An in vitro DCM model was established using doxorubicin (DOX)-treated neonatal mouse cardiomyocytes, and an in vivo model was generated via intraperitoneal DOX administration in mice. Cardiac-specific knockdown of GABRB1 was achieved using AAV9 vectors carrying shRNA under the cardiac troponin T promoter. Mechanistic insights were derived from RNA sequencing, glycosylation assays, and functional validations.

Results: We identified a resident GABAergic network within the human heart and demonstrated upregulated GABRB1 expression in cardiomyocytes from DCM patients, associated with enhanced chromatin accessibility at regulatory regions. Cell–cell communication analysis revealed strengthened interactions between GABAergic neurons and cardiomyocytes in DCM. Both in vitro and in vivo DOX models recapitulated GABRB1 upregulation and DCM phenotypes. Cardiac-specific knockdown of GABRB1 rescued ventricular dilation and systolic dysfunction. Mechanistically, GABRB1 activation drives N-glycosylation of CDH2, disrupting metabolic and neuro-cardiac crosstalk. Glycoproteomic profiling confirmed hyperglycosylation of CDH2 in DCM, and inhibition of glycosylation ameliorated disease progression.

Conclusions: Our findings establish GABRB1 as a central regulator of neuro-cardiac-metabolic dysfunction in DCM, mediated through transcriptional upregulation and post-translational hyperglycosylation of CDH2. Targeted inhibition of GABRB1 or its downstream glycosylation pathway presents a promising therapeutic strategy for restoring autonomic and metabolic homeostasis in DCM.

Dr. Xiangyang Xu is a PhD candidate in Cardiothoracic Surgery at the First Affiliated Hospital of Naval Medical University, specializing in valvular heart disease and cardiomyopathy. His research on postoperative management in high-risk valvular patients has been published in Shock, and he has further contributed to the field with publications in Heart, Lung and Circulation and International Journal of Biological Sciences on aortic dissection and cardiomyopathy, respectively. He has presented his work at a national cardiovascular conference in China. Dr. Xu's current research is focused on the regulatory role of cardiac autonomic nerves in disease progression, underpinned by a robust experimental research platform he has established for dilated cardiomyopathy.