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Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.
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.
Afiliación
  • Feyen DAM; 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.).
  • Perea-Gil I; Departments of Medicine (D.A.M.F., M.V., P.L.A., K.S., M.M.), Stanford University School of Medicine, Stanford University, CA.
  • Maas RGC; 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.).
  • Harakalova M; 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.
  • Gavidia AA; 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.
  • Arthur Ataam J; 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.
  • Wu TH; 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.
  • Vink A; 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.).
  • Pei J; 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.
  • Vadgama N; 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.
  • Suurmeijer AJ; Department of Pathology (A.V.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
  • Te Rijdt WP; 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.
  • Vu M; 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.).
  • Amatya PL; 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.
  • Prado M; Department of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands (A.J.S.).
  • Zhang Y; Netherlands Heart Institute, Utrecht (W.P.t.R.).
  • Dunkenberger L; Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (W.P.t.R.).
  • Sluijter JPG; 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.).
  • Sallam K; Departments of Medicine (D.A.M.F., M.V., P.L.A., K.S., M.M.), Stanford University School of Medicine, Stanford University, CA.
  • Asselbergs FW; 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.).
  • Mercola M; Departments of Medicine (D.A.M.F., M.V., P.L.A., K.S., M.M.), Stanford University School of Medicine, Stanford University, CA.
  • Karakikes I; 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.
Circulation ; 144(5): 382-392, 2021 08 03.
Article en En | MEDLINE | ID: mdl-33928785
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al Calcio / Eliminación de Secuencia / Susceptibilidad a Enfermedades / Respuesta de Proteína Desplegada / Cardiomiopatías Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Circulation Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al Calcio / Eliminación de Secuencia / Susceptibilidad a Enfermedades / Respuesta de Proteína Desplegada / Cardiomiopatías Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Circulation Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos