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

Apr 30, 2021Circulation

Unfolded Protein Response as a Backup Process and Possible Treatment Target in Heart Disease Caused by PLN R14del Mutation

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Abstract

Single-cell RNA sequencing revealed activation of the unfolded protein response (UPR) pathway in PLN R14del cardiomyopathy.

PLN R14del cardiomyopathy models exhibited contractile deficits in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
The unfolded protein response pathway was induced in PLN R14del hiPSC-CMs compared to isogenic controls.
Activation of the UPR was also observed in hearts from PLN R14del patients.
Silencing key UPR signaling branches (IRE1, ATF6, or PERK) worsened contractile dysfunction in PLN R14del hiPSC-CMs.
Treatment with a small molecule activator of the UPR led to a dose-dependent improvement in contractility deficits in PLN R14del hiPSC-CMs.

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

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