The data demonstrate an association between the dose-dependent inhibition of SERCA2a activity by PLN(wt) and the time of onset of heart failure and show that a weak inhibitor of SERCA2a, PLN(R9C), which is diminished in its ability to modify the level of SERCA2a activity, leads to heart failure despite fast sarcoplasmic reticulum Ca(2+) reuptake.
We investigated whether genetic modification of calcium handling through deletion of phospholamban in mice would affect the development of heart failure in mice with transgenic overexpression of the beta1-adrenergic receptor.
The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure.
These results establish this FRET assay as a rapid and quantitative means of screening PLB(M) for optimization of gene therapy to activate SERCA, as needed for gene therapy in HF.
To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide <i>m</i>-chlorophenylhydrazone (CCCP), a mitochondrial membrane potential (MMP)-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL.
These results show that LOF PLB(M) can compete both physically and functionally with PLB(W), provide a rational explanation for the partial success of S16E-based gene therapy in animal models of heart failure, and establish a powerful platform for designing and testing more effective PLB(M) targeted for gene therapy of heart failure in humans.
Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure.
Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure and a poor prognosis from late adolescence.