Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice
| Autor: | Robert D. Gaffin, Beata M. Wolska, Jillian N. Simon, Eric M. Montminy, R. John Solaro, David F. Wieczorek, Chad M. Warren, Marco S.L. Alves |
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| Rok vydání: | 2017 |
| Předmět: |
Cardiomyopathy
Dilated 0301 basic medicine medicine.medical_specialty Myofilament Physiology Mice Transgenic Tropomyosin macromolecular substances 030204 cardiovascular system & hematology Ventricular Myosins 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine Troponin I Myosin medicine Animals Phosphorylation Sensitization Actin Troponin T Chemistry Myocardium Dilated cardiomyopathy Original Articles musculoskeletal system medicine.disease Cyclic AMP-Dependent Protein Kinases Actin Cytoskeleton 030104 developmental biology medicine.anatomical_structure Endocrinology Cardiology Calcium Cardiology and Cardiovascular Medicine |
| Zdroj: | Cardiovascular Research. 113:915-925 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvx068 |
| Popis: | Background Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in α-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype. Methods and results To sensitize Tm54 myofilaments, we used a genetic approach and crossbred Tm54 mice with mice expressing slow skeletal troponin I (ssTnI) that sensitizes myofilaments to Ca2+. Four groups of mice were used: non-transgenic (NTG), Tm54, ssTnI and Tm54/ssTnI (DTG). Systolic function was significantly reduced in the Tm54 mice compared to NTG, but restored in DTG mice. Tm54 mice also showed increased diastolic LV dimensions and HW/BW ratios, when compared to NTG, which were improved in the DTG group. β-myosin heavy chain expression was increased in the Tm54 animals compared to NTG and was partially restored in DTG group. Analysis by 2D-DIGE indicated a significant decrease in two phosphorylated spots of cardiac troponin I (cTnI) in the DTG animals compared to NTG and Tm54. Analysis by 2D-DIGE also indicated no significant changes in troponin T, regulatory light chain, myosin binding protein C and tropomyosin phosphorylation. Conclusion Our data indicate that decreased myofilament Ca2+ sensitivity is an essential element in the pathophysiology of thin filament linked DCM. Sensitization of myofilaments to Ca2+ in the early stage of DCM may be a useful therapeutic strategy in thin filament linked DCM. |
| Databáze: | OpenAIRE |
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