Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 581, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abf0891
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Categories
Funding
- NIH [R01 HL136918, R01 HL063030, R01 HL137259, R01 HL138475, T32 AG058527, R01 HD086026]
- TEDCO [2015-MSCRFI-1622]
- American Heart Association Career Development Award [19CDA34760185, 19CDA34760161]
- Innovative Project Award [18IPA34170446]
- Department of Defense [PR191593]
- Leducq Transatlantic Network of Excellence [16CVD04]
- Leducq [RA15CVD04]
- University of Padova Strategico Grant DYCENDI
- CNR Neuroscience Institute
- Magic That Matters Fund
- Heart Rhythm Society Cardiac Pacing and Electrophysiology Fellowship Award - St. Jude Medical
- Gilead Research Scholars in Cardiovascular Disease Fund
- Dr. Francis P. Chiaramonte Private Foundation
- Foundation Leducq [16CVD02]
- Leyla Erkan Family Fund for ARVD Research
- Bogle Foundation
- Healing Hearts Foundation
- Campanella Family
- Patrick J. Harrison Family
- Peter French Memorial Foundation
- Wilmerding Endowments
- Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins
- [17GRNT33670405]
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Research has shown that in a mouse model mimicking arrhythmogenic cardiomyopathy, myocardial cell death and heart dysfunction are primarily affected by calcium overload and oxidation of apoptosis-inducing factor (AIF). Preventing CAPN1-induced AIF truncation or inhibiting the binding of AIF to the nuclear chaperone PPIA may prevent myocardial cell death and slow down disease progression in ACM and other cardiomyopathies.
Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2(mut/mut)), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2(mut/mut) hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2(mut/mut) mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload-induced necrosis. When cardiomyocytes differentiated from Dsg2(mut/mut) embryonic stem cells (ES-CMs) were challenged with.-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2(mut/mut) ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.
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