Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy
| Autor: | Joshua M. Hare, Brittany Griffin, David Dweck, Jingsheng Liang, Crystal Dawn Badger, Frank D. Fincham, Audrey N. Chang, Raul A Dulce, Jose R. Pinto, Marcos A. Sanchez-Gonzalez, Mohamed Kabbaj, Andrew P. Koutnik, J. Michael Overton, Edda L. Ruiz |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Mice Transgenic macromolecular substances Calsequestrin Biochemistry Sarcomere Muscle hypertrophy Mice Diastole Internal medicine Troponin I medicine Myocyte Animals Myocytes Cardiac cardiovascular diseases Calcium Signaling Phosphorylation Molecular Biology biology Cardiac muscle Hypertrophic cardiomyopathy Molecular Bases of Disease Cell Biology Cardiomyopathy Hypertrophic medicine.disease musculoskeletal system Troponin Cyclic AMP-Dependent Protein Kinases Disease Models Animal Sarcoplasmic Reticulum medicine.anatomical_structure Endocrinology biology.protein cardiovascular system |
| Zdroj: | The Journal of biological chemistry. 289(33) |
| ISSN: | 1083-351X |
| Popis: | The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca(2+) decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca(2+)-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca(2+) transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca(2+) content. This abnormal Ca(2+) handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na(+)-Ca(2+) exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy. |
| Databáze: | OpenAIRE |
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