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.
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