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Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic
Xianming Lin1, Noah Davidsohn2, Sarah Boyce1
1Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, New York, New York.
Background:
Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM) with intracellular calcium dysregulation as a major component of its arrhythmia phenotype. Recent adeno-associated virus (AAV)-based PKP2 gene therapy has shown promising results in a few different PKP2-associated ACM models. Fibroblast growth factor 21 (FGF21) has multiple cardioprotective effects and has recently emerged as a promising therapeutic agent for cardiovascular disease.
Objective:
This study aimed to assess the efficacy and impact on calcium regulation of a novel AAV serotype 8 (AAV8)-based FGF21 gene therapy on adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mice.
Methods:
Experiments were performed using a PKP2-cKO murine model. AAV8-FGF21 was delivered to adult mice by a single tail vein injection 7 days before tamoxifen-activated PKP2-cKO. Cardiac functions were monitored using echocardiography and electrocardiography. Intracellular calcium transients were investigated in acute isolated adult mouse cardiomyocytes, and calcium fluorescent signals were acquired using the IonOptix system.
Results:
Loss of PKP2 expression caused cardiac mechanical dysfunction and proarrhythmic phenotype in adult mouse models. AAV-mediated delivery of FGF21 mitigated the progression of biventricular structural changes, decreased the occurrence of adrenergic arrhythmias, and rescued intracellular calcium imbalance in the setting of PKP2 haploinsufficiency. In contrast, acute in vitro FGF21 treatment for 1 hour had no effect on intracellular calcium transients.
Conclusion:
These beneficial effects of AAV8-FGF21 on the PKP2-ACM phenotype suggest a therapeutic landscape for various targeted cardiomyopathies.
Insights
Adeno-associated virus-mediated fibroblast growth factor 21 (FGF21) gene therapy improved cardiac function and calcium regulation in a mouse model of plakophilin-2 (PKP2) deficiency, offering a potential treatment for arrhythmogenic cardiomyopathy (ACM).
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Molecular Cardiology
Background:
- Pathogenic variants in plakophilin-2 (PKP2) are a primary cause of arrhythmogenic cardiomyopathy (ACM), characterized by intracellular calcium dysregulation and arrhythmias.
- Adeno-associated virus (AAV)-based gene therapy targeting PKP2 has shown promise in ACM models.
- Fibroblast growth factor 21 (FGF21) exhibits cardioprotective properties and is being explored for cardiovascular disease treatment.
Purpose of the Study:
- To evaluate the efficacy of a novel adeno-associated virus serotype 8 (AAV8)-based fibroblast growth factor 21 (FGF21) gene therapy.
- To assess the impact of AAV8-FGF21 on intracellular calcium regulation in an adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mouse model.
Main Methods:
- Experiments utilized a PKP2-cKO murine model.
- Mice received a single tail vein injection of AAV8-FGF21 seven days prior to tamoxifen-induced PKP2 knockout.
- Cardiac function was assessed via echocardiography and electrocardiography; intracellular calcium transients were measured in isolated cardiomyocytes using the IonOptix system.
Main Results:
- PKP2 deficiency led to cardiac mechanical dysfunction and a pro-arrhythmic phenotype in adult mice.
- AAV-mediated FGF21 delivery attenuated biventricular structural changes, reduced adrenergic arrhythmias, and restored intracellular calcium balance in PKP2-haploinsufficient mice.
- Acute in vitro FGF21 treatment did not affect intracellular calcium transients.
Conclusions:
- AAV8-FGF21 gene therapy demonstrates significant beneficial effects on the PKP2-ACM phenotype in a murine model.
- These findings suggest a potential therapeutic strategy for various targeted cardiomyopathies, including those associated with PKP2 deficiency.
