GSE168610
Transcriptomic analyses of cardiomyopathy development in mice carrying the phospholamban p.(Arg14del) pathogenic variant, and comparison with ischemic heart disease
Background: The p.(Arg14del) pathogenic variant (R14del) of the phospholamban (PLN) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model. Methods: We investigated progression of cardiomyopathy in PLN-R14?/? mice using echocardiography, electrocardiography and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 weeks of age (before onset of disease), 5 weeks (mild cardiomyopathy), and 8 weeks (end-stage). Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del-related cardiomyopathy. Results: At 3 weeks of age, PLN-R14?/? mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onwards, ventricular dilatation, decreased contractility and diminished electrocardiogram voltages were observed. Strikingly, PLN protein aggregation was present prior to onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodeling, inflammation and metabolic dysfunction, in part similar to ischemic cardiomyopathy. Altered protein homeostasis pathways were identified exclusively in PLN-R14?/? mice, even before disease onset, in concert with aggregate formation. Conclusions: We mapped the development of PLN-R14del-related cardiomyopathy, and identified alterations in proteostasis and PLN protein aggregation amongst the first manifestations of this disease, which could possibly be a novel target for therapy. Overall design: RNA-Seq on mouse hearts from WT and phospholamban (Pln) R14del mutant mice (3, 5, or 8 weeks old), and ischemic heart diease induced by ischemia-reperfusion (I/R) injury, myocardial infarction (MI) or sham surgery (n=4/group).