Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban
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DOI：
10.1126/science.1081578
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发表时间：
2003-02-28
期刊：
影响因子：
56.9
通讯作者：
Seidman, CE
中科院分区：
文献类型：
--
作者：
Schmitt, JP;Kamisago, M;Seidman, CE
心力衰竭是一种新兴的心血管流行病，影响470万美国人，每年花费178亿美元，其分子病因学仍然知之甚少。在这里，我们报告了遗传性人类扩张型心肌病伴顽固性充血性心力衰竭是由受磷蛋白（PLN）残基9（R9 C）的显性Arg -> Cys错义突变引起的，受磷蛋白是一种跨膜磷蛋白，可抑制心肌肌浆网Ca 2 +-腺苷三磷酸酶（SERCA 2a）泵。转基因PLNR 9 C小鼠重现了人心力衰竭伴过早死亡。细胞和生物化学研究显示，与野生型PLN不同，PLNR 9 C不直接抑制SERCA 2a。相反，PLNR 9 C捕获蛋白激酶A（PKA），其阻断PKA介导的野生型PLN的磷酸化，进而延迟肌细胞中钙瞬变的衰减。这些结果表明，肌细胞钙失调可以启动人类心力衰竭，这一发现可能会导致治疗的机会。
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 PLNR9C mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLNR9C did not directly inhibit SERCA2a. Rather, PLNR9C 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.