期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16604-16609
DOI：10.1073/pnas.1415933111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe main cause of death in autosomal-dominant polycystic kidney disease (ADPKD) patients is cardiac-related. However, the reasons why remain unclear. We show that mice lacking one copy of polycystin 2, a protein mutated in ADPKD, have altered calcium signaling and desensitized calcium-contraction coupling in cardiomyocytes. We also show that decreased polycystin 2 levels affect cardiac function by altering responses to adrenergic stimulus. We propose that altering polycystin levels in the heart directly contributes to remodeling of the heart in patients with ADPKD in the absence of renal failure or high blood pressure. Cardiac disorders are the main cause of mortality in autosomal-dominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2+/-) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2+/- cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2+/- mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2+/- mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a {beta}-adrenergic receptor ({beta}AR) agonist. Blockers of {beta}AR-1 and {beta}AR-2 inhibited the ISO response in Pkd2+/- mice, suggesting that the dephosphorylated state of PLB is primarily by {beta}AR-2 signaling. Importantly, the Pkd2+/- mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the {beta}AR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.
