Project Details
Projekt
The role of phospholamban pentamers in the diseased heart
Subject Area
Pharmacology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564272539
Heart failure affects around 3.3 million people in Germany and its prevalence is rising. Despite therapeutic advances, there is a continuing need for new and effective treatments, as the survival rate for heart failure is comparable to that of malignant tumours. Disturbances of cardiomyocyte Ca2+ cycling play a causal role in the pathogenesis of heart failure and, thus, represent a promising therapeutic target both in heart failure with reduced and with preserved ejection fraction. Nevertheless, to date, not a single drug has been approved for the treatment of chronic heart failure that directly targets the regulation of cardiomyocyte Ca2+ cycling. We recently demonstrated that phospholamban (PLN) in its pentameric form constitutes a preferred substrate of protein kinase A (PKA) and attenuates PKA-dependent phosphorylation of PLN monomers, the endogenous inhibitors of the sarcoplasmic Ca2+-ATPase SERCA2a. Subsequent investigation of the functional consequences revealed that PLN pentamers attenuate SERCA2a activity under basal conditions, but allow maximum activity upon adrenergic stimulation. Thereby, PLN pentamers extend the range of regulatory possibilities of myocyte Ca2+ cycling and sarcomere function by SERCA2a. Importantly, PLN pentamerization improved the adaptation of mouse hearts to chronic left ventricular pressure overload. We now aim to clarify why PLN pentamers improved myocardial function, attenuated cardiac hypertrophy and interstitial fibrosis, and prolonged survival in hypertensive heart disease by performing comprehensive analyses of cardiomyocyte Ca2+ regulation, sarcomere function, bioenergetics, fibroblast communication, immune cell responses, and single cell transcriptomics (work package 1). As previously demonstrated in our research, phosphorylation of PLN monomers is reduced early after regional ischemia/reperfusion injury of the heart also in the non-ischemic areas (remote myocardium), and the consecutive impairment of cardiomyocyte Ca2+ cycling is an underlying cause of sarcomere dysfunction and may lead to heart failure after myocardial infarction. We thus aim to explore how suppression of PLN pentamerization can counteract excessive SERCA2a inhibition in the remote myocardium and thereby improve functional and structural adaptation of the heart after ischemia/reperfusion injury (work package 2). We further found that a PLN mutant, PLN-AFA, can recruit PLN monomers from PLN pentamers and thereby decrease the pentamer-to-monomer ratio. Therefore, we expect the AFA sequence to guide us to minimal-length peptide sequences that selectively alter the PLN pentamer-to-monomer ratio when added to wildtype PLN. Based on these peptide sequences, we foresee the design of peptidomimetic compounds that could provide promising new tools against heart failure by targeted modulation of SERCA2a activity (work package 3).
DFG Programme
Research Grants
Co-Investigators
Professor Dr. Holger Gohlke; Dr. Jochen Hecht; Professor Dr. André Heinen
