Mechanisms driving cardiac dysfunction in Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病心脏功能障碍的驱动机制

基本信息

批准号：
10443441
负责人：
Francisco Altamirano
金额：
$ 40.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443441
关键词：
Ablation Action Potentials Affect Age Alleles Automobile Driving Autosomal Dominant Polycystic Kidney Biochemical Ca(2+)-Transporting ATPase Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cells Clinical Complement Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dose Economic Burden Electrophysiology (science)Event Exhibits Functional disorder Gene Mutation Genes Heart Heart Diseases Heart failure Hereditary Disease Histologic Human Hypertension Impairment In Vitro Individual Intervention Kidney Kidney Diseases Kidney Failure Knock-in Kv channel-interacting protein 2 Left Longevity Methods Modeling Molecular Monitor Morbidity - disease rate Mus Mutation Myocardial dysfunction NG-Nitroarginine Methyl Ester Pathway interactions Patients Persons Pharmacology Potassium Potassium Channel Predisposition Process Proteins Quality of life Regulation Reporting Role Sarcoplasmic Reticulum Signal Transduction Techniques Testing Time Ventricular Ventricular Dysfunction base comorbidity defined contribution health care economics heart function improved in vivo induced pluripotent stem cell derived cardiomyocytes insight kidney cell kidney dysfunction knock-down mortality mouse model mutant novel overexpression phospholamban polycystic kidney disease 1 protein renal epithelium sarcoplasmic reticulum calcium ATPase small molecule

项目摘要

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.

心血管疾病是常染色体显性多囊肾脏疾病（ADPKD）患者发病率和死亡率的主要原因。 ADPKD以进行性肾功能障碍为特征，不可能是非常重要的医疗保健和经济伯内斯。通常认为进行性肾功能障碍会促进心脏病。但是，我们的初步数据表明心脏功能障碍起源于心肌细胞和ADPKD肾衰竭之前的表现。最近的临床证据支持我们的发现，表明ADPKD患者即使在非高血压个体中，ADPKD患者即使在肾衰竭发作之前也暴露了心室功能障碍。编码多囊1（PC1）的基因中的突变发生在85％的患者中，并导致最严重的病例。重要的是，PC1在心肌细胞中表达，但其作用却很少。我们建议，突变体PC1（以心肌自治方式）引发并驱动ADPKD中的心脏病，与肾衰竭无关。我们的数据表明，PC1心肌细胞特异性缺失可促进小鼠的收缩和舒张功能障碍。此外，使用具有临床上建立的ADPKD引起PC1突变（RC等位基因）的小鼠模型，我们提供了在肾衰竭之前发生的心肌细胞水平下钙 - 偶联和收缩力受损的证据。杂合RC/+年轻小鼠在分离的心肌细胞中表现出钙处理/收缩性的改变，这与左心室全球纵向菌株和舒张功能障碍的减少相关。我们发现PC1通过KV通道电流调节调节动作潜在持续时间。 PC1消融可缩短动作潜在的持续时间，并损害心肌细胞中的钙瞬变和收缩力。此外，PC1缺失会损害通过降低的SR钙ATPase（SERCA）活性，损害了肌浆网（SR）钙负载。这些数据使我们假设引起ADPKD的PC1突变破坏了心肌细胞中的PC1作用，损害心脏功能并使心脏易于高血压诱导的心力衰竭，而与肾功能障碍无关。为了检验这一假设，我们提出了三个目的：1）确定PC1突变如何影响动作电位和KV通道活动，并影响钙处理和收缩力。 2）阐明PC1调节SR钙负载和SERCA以维持心肌细胞功能并测试ADPKD突变对PC1对这些事件的影响。 3）在体内确定心肌细胞中PC1信号传导的改变是否会驱动心脏功能障碍，并使心脏倾向于高血压引起的心力衰竭。我们的研究的完成将提供有关驱动心脏病在ADPKD中的心肌自治事件的作用的范式转移信息，ADPKD是这些患者的主要死亡原因。