Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

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.

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…Despite decades of research, heart failure remains a major cause of death and mortality32333435363738. Therefore, improved understanding of the molecular mechanisms underlying heart failure is still urgently needed to develop novel targeted treatment strategies.…”

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

“…Thus, an alteration in the PLB: SERCA ratio can affect SR Ca 2+ transport. More recently, studies in human suggest that mutations in PLB [43,44] or the absence of PLB [45] can cause far more serious functional consequences, culminating in human heart failure. It is tempting to speculate that, in larger mammals PLB is essential for maintaining heart function, unlike in mouse.…”

Multidimensional protein identification technology (MudPIT): Technical overview of a profiling method optimized for the comprehensive proteomic investigation of normal and diseased heart tissue

“…To account for biological complexity, multiple validated mouse models of cardiomyopathy have been chosen for detailed study. We are currently completing an exhaustive evaluation of the proteomic patterns of heart tissue in transgenic mice carrying specific point mutations in a key regulatory protein, phospholamban, in comparison to those recorded with age-matched wild-type animals, tracking different stages as these animals progress to severe dilated cardiomyopathy,°hypertrophy,°and°heart°failure° [7]. One°key°objective of the data analysis is to identify interesting candidates that appear to be mechanistically linked to disease progression arising from this study for follow up analysis using traditional molecular genetic methods.…”

“…For instance, transgenic mice overexpressing a human disease point mutant variant in PLN (R9C) die early of severe dilated cardiomyopathy (within four to five months of age). It is possible to examine the phenotype of the affected cardiac tissue of such mice at various stages of pathology, even prior to overt presentation of clinical symptoms, and to examine the corresponding proteome at select time-points in the disease progression using shotgun proteomic approaches [7]. When this potential is combined with the use of high penetrance inbred strains to minimize the influence of genetic variance, a more refined investigation of the course of disease action can be carried out.…”