Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy

• Published in: Circulation (New York, N.Y.) Vol. 144; no. 5; pp. 382 - 392
• Main Authors: Feyen, Dries A.M., Perea-Gil, Isaac, Maas, Renee G.C., Harakalova, Magdalena, Gavidia, Alexandra A., Arthur Ataam, Jennifer, Wu, Ting-Hsuan, Vink, Aryan, Pei, Jiayi, Vadgama, Nirmal, Suurmeijer, Albert J., te Rijdt, Wouter P., Vu, Michelle, Amatya, Prashila L., Prado, Maricela, Zhang, Yuan, Dunkenberger, Logan, Sluijter, Joost P.G., Sallam, Karim, Asselbergs, Folkert W., Mercola, Mark, Karakikes, Ioannis
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 03.08.2021
• Subjects: Adaptation, Physiological; Biomarkers; Calcium-Binding Proteins - genetics; Cardiomyopathies - diagnosis; Cardiomyopathies - drug therapy; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - physiopathology; Culture Media, Conditioned - metabolism; Culture Media, Conditioned - pharmacology; Disease Management; Disease Susceptibility; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells - metabolism; Molecular Targeted Therapy; Myocardial Contraction - drug effects; Sequence Deletion; Single-Cell Analysis; Transcriptome; Unfolded Protein Response; unfolded protein response; induced pluripotent stem cells; models, biological; phospholamban; sequence analysis, RNA; cardiomyopathy, dilated
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.120.049844

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. 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. 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. 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.