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27 April 2024 |
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Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban | | 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
; | | Date: |
28 Feb 2003 | | Journal: | Science, 299 (5611), 1410-3 | | Abstract: | 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. | | Source: | PubMed, pmid12610310 doi: 10.1126/science.1081578 | | Services: | Forum | Review | Favorites | |
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