Mechanisms driving cardiac dysfunction in Autosomal Dominant Polycystic Kidney Disease

心血管疾病是常染色体显性遗传性多囊肾病（ADPKD）患者发病和死亡的主要原因。以进行性肾功能不全为特征的ADPKD造成了非常严重的医疗保健和经济负担。通常认为进行性肾损害促进心脏病;然而，我们的初步数据表明，心功能不全起源于心肌细胞，并在ADPKD肾衰竭之前表现出来。最近的临床证据支持我们的研究结果，显示ADPKD患者在肾衰竭发作前表现出心室功能障碍，即使在非高血压个体中也是如此。编码多囊蛋白-1（PC 1）的基因突变发生在85%的患者中，并且是最严重病例的原因。重要的是，PC 1在心肌细胞中表达，但其作用却知之甚少。我们认为突变型PC 1以心肌细胞自主的方式启动并驱动ADPKD患者的心脏病，与肾衰竭无关。我们的数据表明，PC 1心肌细胞特异性缺失促进小鼠的收缩和舒张功能障碍。此外，使用一个小鼠模型窝藏一个临床上建立的ADPKD引起的PC 1突变（RC等位基因），我们提供的证据表明，受损的钙循环和心肌细胞水平的收缩力，这发生在肾功能衰竭发作之前。杂合子RC/+年轻小鼠表现出在离体心肌细胞中钙处理/收缩性的改变，这与左心室整体纵向应变和舒张功能障碍的降低相关。我们发现，PC 1通过Kv通道电流调节来调节动作电位时程。PC 1消融缩短了动作电位时程，并损害了心肌细胞的钙瞬变和收缩性。此外，PC 1缺失通过降低肌浆网（SR）钙-ATP酶（SERCA）活性损害SR钙负荷。这些数据使我们假设ADPKD引起的PC 1突变破坏了心肌细胞中的PC 1作用，损害了心脏功能，使心脏易患高血压诱导的心力衰竭，与肾功能不全无关。为了验证这一假设，我们提出了三个目标：1）确定PC 1突变如何影响动作电位和Kv通道活性，并影响钙处理和收缩性。2)阐明PC 1调节SR钙负荷和SERCA以维持心肌细胞功能的机制，并测试PC 1中ADPKD突变对这些事件的影响。3)在体内确定心肌细胞中PC 1信号传导的改变是否会导致心脏功能障碍并使心脏容易发生高血压诱导的心力衰竭。我们研究的完成将提供关于心肌细胞自主事件驱动心脏病在ADPKD中的作用的范式转变信息，ADPKD是这些患者死亡的主要原因。

Cardiovascular disease is a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Characterized by progressive renal dysfunction, ADPKD imposes very significant healthcare and economic burdens. It has commonly been assumed that progressive renal impairment promotes cardiac disease; however, our preliminary data suggest that cardiac dysfunction originates in cardiomyocytes and manifests prior to renal failure in ADPKD. Recent clinical evidence supports our findings by showing that ADPKD patients exhibit ventricular dysfunction before the onset of renal failure, even in non-hypertensive individuals. Mutations in the gene encoding Polycystin-1 (PC1) occur in 85% of patients and are responsible for the most severe cases. Importantly, PC1 is expressed in cardiomyocytes, yet its role(s) there is(are) poorly understood. We propose that the mutant PC1 – in a cardiomyocyte-autonomous fashion – initiates and drives heart disease in ADPKD, independent of renal failure. Our data show that PC1 cardiomyocyte-specific deletion promotes systolic and diastolic dysfunction in mice. Furthermore, using a mouse model harboring a clinically established ADPKD-causing PC1 mutation (RC allele), we provide evidence of impaired calcium-cycling and contractility at the cardiomyocyte level, which occur before the onset of renal failure. Heterozygous RC/+ young mice manifest alterations in calcium handling/contractility in isolated cardiomyocytes, which correlate with reduced left ventricular global longitudinal strain and diastolic dysfunction. We discovered that PC1 regulates action potential duration via Kv channel current regulation. PC1 ablation shortens action potential duration and impairs both calcium transients and contractility in cardiomyocytes. Additionally, PC1 deletion impairs sarcoplasmic reticulum (SR) calcium loading through reduced SR calcium-ATPase (SERCA) activity. These data have led us to hypothesize that ADPKD-causing PC1 mutations disrupt PC1 actions in cardiomyocytes, impair cardiac function and predispose the heart to hypertension-induced heart failure, independent of renal dysfunction. To test this hypothesis, we propose three aims: 1) determine how PC1 mutations affect action potentials and Kv channel activity and impinge on calcium handling and contractility. 2) elucidate mechanisms whereby PC1 regulates SR calcium loading and SERCA to maintain cardiomyocyte function and test the impact of ADPKD mutations in PC1 on these events. 3) determine in vivo whether alterations in PC1 signaling in cardiomyocytes drive cardiac dysfunction and predispose the heart to hypertension-induced heart failure. Completion of our studies will provide paradigm-shifting information regarding the role of cardiomyocyte-autonomous events driving heart disease in ADPKD, the leading cause of death in these patients.