BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood. METHODS Using protein mass spectrometry analyses, we identified that integrin β1 is downregulated in ARVC hearts without changes to Ca2+-handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin β1D loss on function in the heart in vivo and in vitro. RESULTS Integrin β1D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, β1D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca2+ handling in β1D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin β1D deficiency in ARVC mediated through an ERK1/2 (extracellular signal-regulated kinase 1 and 2)-fibronectin-ubiquitin/lysosome pathway. CONCLUSIONS Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.

中文翻译：

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整合素β1D缺乏介导的RyR2功能障碍导致心律失常性右心室心肌病的儿茶酚胺敏感性心动过速。

背景技术致心律失常性右心室心肌病（ARVC）是一种遗传性心脏病，其特征在于脂肪浸润，危及生命的心律不齐，并增加了心脏猝死的风险。对患者进行ARVC的指导原则是通过减少心律不齐症状来改善生活质量并防止心源性猝死。然而，ARVC相关的心律不齐的潜在机制仍知之甚少。方法使用蛋白质质谱分析，我们发现整联蛋白β1在ARVC心脏中被下调，而没有改变Ca2 +处理蛋白。由于成年心肌细胞仅表达β1D亚型，我们生成了心脏特异性β1D基因敲除小鼠模型，并进行了功能成像和生化分析，以确定体内和体外整合素β1D缺失对心脏功能的影响。结果通过Western印迹法在ARVC患者的左心室组织中检测到了整合素β1D缺乏和RyR2 Ser-2030过度磷酸化，但在缺血性或肥厚性心肌病患者中未检测到。使用脂质双层膜片钳单通道记录，我们发现纯化的整合素β1D蛋白可以通过降低RyR2打开概率，平均打开时间和增加平均关闭时间来稳定RyR2功能。此外，β1D基因敲除小鼠表现出正常的心脏功能和形态，但表现为儿茶酚胺敏感的多形性室性心动过速，与增加的RyR2 Ser-2030磷酸化和异常的Ca2 +处理在β1D基因敲除的心肌细胞中一致。从机理上讲，我们发现DSP的缺失（去氨铂）可通过ERK1 / 2（细胞外信号调节激酶1和2）-纤连蛋白-泛素/溶酶体途径介导ARVC的整联蛋白β1D缺乏。结论我们的数据表明，整合素β1D缺乏代表了ARVC患者室性心律失常风险增加的新机制。