Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

American Association for the Advancement of Science (AAAS) - Tập 299 Số 5611 - Trang 1410-1413 - 2003
Joachim P. Schmitt1, Mitsuhiro Kamisago2,1, Michio Asahi3, Guo Hua Li1, Ferhaan Ahmad1, Ulrike Mende2, Evangelia G. Kranias4, David H. MacLennan3, J G Seidman1, Christine E. Seidman2,1
1Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
2Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
3Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G1L6, Canada.
4Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267 USA

Tóm tắt

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 Ca 2+ –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.

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We thank J. Robbins for the αMHC promoter vector R. J. Kauffman for the pMT2 vector R. G. Johnson for the 1D11 and 285 antibodies and X. Xu for preparation of myocytes. Supported by NIH the Henrietta and Frederick Bugher Fund the Heart and Stroke Foundation of Ontario the Canadian Genetic Diseases Network of Centers of Excellence and the Canadian Institutes of Health Research.

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American Association for the Advancement of Science (AAAS)

Tập 299 Số 5611

1410-1413

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