Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy-Reference-Cited by-同舟云学术

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

Published:2021-08-03 Issue:5 Volume:144 Page:382-392
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Feyen Dries A.M.¹²,Perea-Gil Isaac¹³,Maas Renee G.C.⁴^ORCID,Harakalova Magdalena⁴^ORCID,Gavidia Alexandra A.³^ORCID,Arthur Ataam Jennifer¹³^ORCID,Wu Ting-Hsuan³,Vink Aryan⁵^ORCID,Pei Jiayi⁴,Vadgama Nirmal¹³^ORCID,Suurmeijer Albert J.⁶,te Rijdt Wouter P.⁷⁸^ORCID,Vu Michelle¹²^ORCID,Amatya Prashila L.¹²^ORCID,Prado Maricela³,Zhang Yuan³^ORCID,Dunkenberger Logan³,Sluijter Joost P.G.⁴,Sallam Karim¹²,Asselbergs Folkert W.⁴⁹¹⁰¹¹,Mercola Mark¹²,Karakikes Ioannis¹³^ORCID

Affiliation:

1. Cardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).

2. Departments of Medicine (D.A.M.F., M.V., P.L.A., K.S., M.M.), Stanford University School of Medicine, Stanford University, CA.

3. Cardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.

4. Department of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.

5. Department of Pathology (A.V.), University Medical Center Utrecht, University of Utrecht, The Netherlands.

6. Department of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands (A.J.S.).

7. Netherlands Heart Institute, Utrecht (W.P.t.R.).

8. Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (W.P.t.R.).

9. Institute of Cardiovascular Science, Faculty of Population Health Sciences (F.W.A.), University College London, UK.

10. Health Data Research UK (F.W.A.), University College London, UK.

11. Institute of Health Informatics (F.W.A.), University College London, UK.

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.049844

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