159 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 First author and year of publication Species Type of study Main findings Balducci (2023)107 hiPSC in vitro, model characterisation Study generated hiPSC lines from five PLN-R14del carriers who were asymptomatic at the time of blood collection and one non-carrier family member. All six lines show the correct characterisation of pluripotency. Stege (2023)108 Mouse Clinical examination, Pathological examination, functional readout, ex vivo Dwarf open reading frame (DWORF) overexpression delayed cardiac fibrosis, heart failure and increased life span >2-fold by reducing abnormal ER clusters in homozygous R14del mice. Van der Voorn (2023)109 Human Genotyping array cohort study for HRC polymorphism frequencies The p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failurerelated events of 848 PLN-R14del carriers. Abbreviations: ACM = Arrhythmogenic Cardiomyopathy; ASO= antisense oligonucleotides; APD = Action Potential Duration; ASO=AntiSense Oligonucleotides; Ca2+ = Calcium; CaMKII = Calmodulin dependent kinase II; CM = Cardiomyocyte; CMR = Cardiac Magnetic Resonance; DCM = Dilated Cardiomyopathy; DNN= Deep Neural Network; ECG = Electrocardiogram; EHT = Engineered heart tissue; ER = Endoplasmic Reticulum; FAO = fatty acid oxidation; HCM = Hypertropic Cardiomyopathy; HF = Heart Failure; HRC = histidine-rich Ca2+ binding; ICD = Implantable Cardioverter-Defibrillator; iPSC = induced Pluripotent Stem Cell; LV = left ventricle; LVEF = Left Ventricular Ejection Fraction; LPW = left posterolateral wall; LVMD = Left Ventricular Mechanical Dispersion; NKA = Na/K-ATPase; PC = peripartum cardiomyopathy; PLN = Phospholamban; PLN-R14del/p.Arg14del = Deletion of arginine 14 in PLN gene; Preprint = manuscripts published on BioRxiv or ResearchSquare. PSS = Post-Systolic Shortening; RV =Right Ventricle; SCD = Sudden Cardiac Death; SERCA2a = Sarco/endoplasmic reticulum Ca2+- ATPase 2a; TALENs= Transcription Activator Like Effector Nucleases; TF= Transcription Factor; TFC = Task Force Criteria; UPR = Unfolded Protein Response; VA = Ventricular Arrhythmia; VT = Ventricular tachycardia. Cellular and molecular alterations in PLN-R14del Cardiomyopathy The major features of PLN-R14del disease that could be linked to the pathogenic mutation include cellular and molecular dysfunctions such as protein aggregation/toxicity, arrhythmogenesis, metabolic dysfunction, reduced cardiac function, fibrosis, resulting in a structural cardiomyopathy phenotype. However, the contributing mechanisms underlying these PLN-R14del pathophysiological features remain unclear. Here, we review the current knowledge on how PLN-R14del mutation causes the panoply of DCM and ACM manifestations and the potential molecular mechanisms contributing to the disease pathophysiology. Calcium cycling and contractile force. The PLN protein is a crucial regulator of cardiac contractility by modulating calcium (Ca2+) transport via SERCA2a and its functioning has been extensively reviewed.110 In brief, when dephosphorylated, PLN binds to SERCA2a through intramembrane protein-protein interactions to lower its affinity for Ca2+, thereby decreasing the Ca2+ uptake into the sarcoplasmic reticulum (SR), which results in the contraction of the cardiomyocyte.111,112 Phosphorylation of PLN reverses this inhibition, stimulating calcium transport into the SR and increasing the rate of relaxation. PLN phosphorylation is regulated by protein kinase A (PKA)
RkJQdWJsaXNoZXIy MTk4NDMw