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Abstract P3130: Preventing Site-specific Calpain Cleavage Of Junctophilin-2 Protects Against Stress-induced E-c Coupling Dysfunction And Heart Failure Development In Mice
Abstract only In heart failure (HF), excitation-contraction (E-C) coupling processes become disrupted, resulting in abnormal Ca 2+ homeostasis that triggers cardiac dysfunction. Junctophilin-2 (JP2) is an essential E-C coupling constituent for maintaining cardiomyocyte integrity and cardiac function...
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Published in: | Circulation research 2023-08, Vol.133 (Suppl_1) |
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Main Author: | |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Abstract only
In heart failure (HF), excitation-contraction (E-C) coupling processes become disrupted, resulting in abnormal Ca
2+
homeostasis that triggers cardiac dysfunction. Junctophilin-2 (JP2) is an essential E-C coupling constituent for maintaining cardiomyocyte integrity and cardiac function both at baseline and in response to stress. We previously showed that calpain-mediated proteolytic cleavage of JP2 at arginine 565 / threonine 566 (R
565
/T
566
) is key to its downregulation in the diseased heart. However, it remains unclear whether preventing site-specific proteolysis of JP2 can prevent cardiac remodeling and HF progression following stress. To investigate this, calpain-resistant mutant JP2 knockin mice (JP2
CR
) were generated by deleting residues 563-568 spanning the primary calpain cleavage site. Studies in cultured cardiomyocytes treated with isoproterenol (ISO) showed that JP2
CR
is resistant to stress-induced loss of JP2 integrity and T-tubule disorganization compared to wild-type (WT) cardiomyocytes. Further, in vivo studies demonstrate JP2
CR
mice are more resistant to pressure overload stress having significantly less abnormal Ca
2+
homeostasis, cardiac dysfunction, hypertrophy, lung edema and fibrosis relative to WT mice. Western blot analysis revealed JP2
CR
hearts have preserved expression levels of several key E-C coupling proteins, including RyR2, SERCA2a and Ca
V
1.2. RNA-Sequencing analysis further revealed attenuated pressure overload induced hypertrophic and heart failure-related transcriptional reprogramming in JP2
CR
hearts. These findings indicate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain-cleavage of JP2 offers cardiac protection against stress-induced hypertrophy and heart failure. Our data indicate that preventing JP2 cleavage by gene therapy approaches may hold great therapeutic potential for treating heart failure. |
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ISSN: | 0009-7330 1524-4571 |
DOI: | 10.1161/res.133.suppl_1.P3130 |