1. Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy
- Author
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Prashila L Amatya, Mark Mercola, Jennifer Arthur Ataam, Michelle Vu, Alexandra A Gavidia, Renee G.C. Maas, Wouter P. te Rijdt, Ting-Hsuan Wu, Maricela Prado, Albert J. H. Suurmeijer, Ioannis Karakikes, Logan Dunkenberger, Joost P.G. Sluijter, Isaac Perea-Gil, Nirmal Vadgama, Aryan Vink, Yuan Zhang, Jiayi Pei, Karim Sallam, Magdalena Harakalova, Dries A.M. Feyen, Folkert W. Asselbergs, Cardiology, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Arginine ,sequence analysis ,Cardiomyopathy, Dilated/genetics ,Cardiomyopathy ,Regulator ,030204 cardiovascular system & hematology ,ACTIVATION ,0302 clinical medicine ,ENDOPLASMIC-RETICULUM STRESS ,Molecular Targeted Therapy ,Sequence Deletion ,0303 health sciences ,INDUCTION ,Disease Management ,unfolded protein response ,MOUSE MODEL ,ER STRESS ,Culture Media, Conditioned/metabolism ,Adaptation, Physiological ,Phospholamban ,Cell biology ,DIFFERENTIATION ,HEART ,Disease Susceptibility ,Myocardial Contraction/drug effects ,Single-Cell Analysis ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,PHOSPHOLAMBAN ,dilated ,Cardiomyopathy, Dilated ,endocrine system ,induced pluripotent stem cells ,PROTEOSTASIS ,Physiological ,Article ,Contractility ,Cardiomyopathies/diagnosis ,03 medical and health sciences ,models ,Physiology (medical) ,medicine ,Humans ,Genetic Predisposition to Disease ,Adaptation ,030304 developmental biology ,Calcium-Binding Proteins/genetics ,business.industry ,Mechanism (biology) ,Gene Expression Profiling ,Calcium-Binding Proteins ,medicine.disease ,Myocardial Contraction ,GENE ,Culture Media ,Induced Pluripotent Stem Cells/metabolism ,Proteostasis ,Dilated/genetics ,Culture Media, Conditioned ,Unfolded protein response ,RNA ,business ,Transcriptome ,cardiomyopathy ,Biomarkers ,Conditioned/metabolism ,biological - Abstract
Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies. Methods: We used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs. Results: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis. Conclusions: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.
- Published
- 2021