Proteomic analysis of the aging sinoatrial node identified 528 differentially expressed proteins, and overexpression of Itgbl1 in SAN fibroblasts decreased heart rate and reduced HCN4 expression.
Does Itgbl1 overexpression affect heart rate and HCN4 expression in the sinoatrial node of animal models?
Itgbl1 is identified as a potential therapeutic target for age-related sinoatrial node dysfunction, as its overexpression in SAN fibroblasts decreases heart rate and reduces HCN4 expression.
Abstract Background Aging affects various physiological systems, including the cardiovascular system. The sinoatrial node (SAN), the heart's natural pacemaker, undergoes structural and functional changes with age, leading to a decreased heart rate and compromised cardiovascular health. Despite known age-related alterations, mechanistic data, particularly at the protein level, are limited. This study aims to elucidate the proteomic changes in the aging SAN and explore potential therapeutic targets for SAN-related diseases. Methods Adult male Wistar rats (young, 3 months; old, 25 months) were used to study heart rate differences and protein expression changes in the SAN. High-resolution mass spectrometry quantified protein abundances in young and aging SAN tissues. Additional experiments included immunohistochemistry, immunofluorescence, Tbx18-induced pacemaker cell model, real-time RT-PCR, and western blot analysis. AAV9 vectors mediated gene transfer in mice to study the effects of integrin subunit beta-like 1 (Itgbl1) overexpression on heart rate. Results Aging rats exhibited a significantly lower heart rate compared to young rats. Proteomic analysis identified 5936 quantifiable proteins, with 528 showing significant differential expression between young and old SAN. Key findings include decreased expression of pacemaking ion channels (e.g., HCN4), altered metabolic pathways favoring glucose metabolism over fatty acid oxidation, increased extracellular matrix (ECM) components, and structural remodeling indicative of fibrosis and hypertrophy. Itgbl1, a protein associated with fibroblast activation, showed increased expression in fibroblast of aging SAN. Overexpression of Itgbl1 in fibroblast of SAN decreased heart rate and reduced HCN4 expression, suggesting its role in rhythm regulation. Conclusion This study provides a comprehensive proteomic analysis of the aging SAN, highlighting significant age-dependent changes in protein expression, ion channel composition, metabolic pathways, and ECM organization. The increased expression of Itgbl1 and its impact on heart rate and SAN structure identifies it as a potential therapeutic target for age-related SAN dysfunction. Further research is needed to explore the detailed mechanisms of Itgbl1's role in SAN aging and its potential for therapeutic intervention.
Chen et al. (2025) studied Aging sinoatrial node dysfunction. Itgbl1 overexpression via AAV9 vectors vs. Young rats / control was evaluated on Heart rate and protein expression changes in the SAN. Proteomic analysis of the aging sinoatrial node identified 528 differentially expressed proteins, and overexpression of Itgbl1 in SAN fibroblasts decreased heart rate and reduced HCN4 expression.