دورية
Interplay between Triadin and Calsequestrin in the Pathogenesis of CPVT in the Mouse
| العنوان: | Interplay between Triadin and Calsequestrin in the Pathogenesis of CPVT in the Mouse |
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| المؤلفون: | Cacheux, Marine, Fauconnier, Jérémy, Thireau, Jérôme, Osseni, Alexis, Brocard, Jacques, Roux-Buisson, Nathalie, Brocard, Julie, Fauré, Julien, Lacampagne, Alain, Marty, Isabelle |
| المصدر: | Molecular Therapy; January 2020, Vol. 28 Issue: 1 p171-179, 9p |
| مستخلص: | Recessive forms of catecholaminergic polymorphic ventricular tachycardia (CPVT) are induced by mutations in genes encoding triadin or calsequestrin, two proteins that belong to the Ca2+release complex, responsible for intracellular Ca2+release triggering cardiac contractions. To better understand the mechanisms of triadin-induced CPVT and to assay multiple therapeutic interventions, we used a triadin knockout mouse model presenting a CPVT-like phenotype associated with a decrease in calsequestrin protein level. We assessed different approaches to rescue protein expression and to correct intracellular Ca2+release and cardiac function: pharmacological treatment with kifunensine or a viral gene transfer-based approach, using adeno-associated virus serotype 2/9 (AAV2/9) encoding the triadin or calsequestrin. We observed that the levels of triadin and calsequestrin are intimately linked, and that reduction of both proteins contributes to the CPVT phenotype. Different combinations of triadin and calsequestrin expression level were obtained using these therapeutic approaches. A full expression of each is not necessary to correct the phenotype; a fine-tuning of the relative re-expression of both triadin and calsequestrin is required to correct the CPVT phenotype and rescue the cardiac function. AAV-mediated gene delivery of calsequestrin or triadin and treatment with kifunensine are potential treatments for recessive forms of CPVT due to triadin mutations. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 15250016 15250024 |
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| DOI: | 10.1016/j.ymthe.2019.09.012 |