Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

作者：Joachim P. Schmitt, Mitsuhiro Kamisago, Michio Asahi, Guo Hua Li, Ferhaan Ahmad, Ulrike Mende, Evangelia G. Kranias, David H. MacLennan, J G Seidman, Christine E. Seidman · 发表于：Science · 年份：2003 · DOI：10.1126/science.1081578 · 被引用次数：633 · 研究领域：Cardiac electrophysiology and arrhythmias、Cardiomyopathy and Myosin Studies、Ion channel regulation and function

Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.