Aims In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. Methods and results We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Conclusion Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

中文翻译：

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蛋白质组学将电重塑与窦房结功能障碍小鼠心力衰竭模型中的炎症联系起来

目的 对于心力衰竭 (HF) 患者，伴随的窦房结功能障碍 (SND) 是死亡率的重要预测因素，但其分子基础尚不清楚。本研究旨在利用蛋白质组学来剖析 HF 并发 SND 动物模型中窦房结内的蛋白质和磷酸化重塑。方法和结果 我们获得了心力衰竭和 SND 小鼠的深部窦房结蛋白质组和磷酸化蛋白质组，并报告了广泛的重塑。将测得的（磷酸）蛋白质组变化与人类基因组药物警戒数据相交叉，突出显示了参与电活动的下调蛋白质，例如起搏器离子通道 Hcn4。我们使用计算机建模证实了离子通道下调对窦房结生理学的重要性。在蛋白质组学数据的指导下，我们假设炎症反应可能驱动心力衰竭中 SND 的电生理重塑。为了支持这一点，实验诱导的炎症下调了 Hcn4 并减慢了孤立窦房结的起搏速度。根据蛋白质组学数据，我们确定促炎细胞因子样蛋白半乳糖凝集素 3 是减轻该影响的潜在靶点。事实上，在心力衰竭动物模型中体内抑制半乳糖凝集素 3 可以预防 SND。结论 总的来说，我们概述了心力衰竭中 SND 的蛋白质和磷酸化重塑，强调了炎症在窦房结电生理重塑中的作用，并提出了半乳糖凝集素 3 信号传导作为改善心力衰竭中 SND 的靶标。