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Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites.
- Source :
-
Circulation research [Circ Res] 2004 Mar 05; Vol. 94 (4), pp. 496-504. Date of Electronic Publication: 2004 Jan 15. - Publication Year :
- 2004
-
Abstract
- Acute beta-adrenergic stimulation enhances cardiac contractility, accelerates muscle relaxation, and amplifies the inotropic and lusitropic response to increased stimulation frequency. These effects are modulated by phosphorylation of calcium handling and myofilament proteins such as troponin I (TnI) by protein kinase A (PKA). To more directly delineate the role of TnI PKA phosphorylation, transgenic mice were generated that overexpress cardiac TnI in which the serine residues normally targeted by PKA are mutated to aspartic acid to mimic constitutive phosphorylation (TnIDD22,23). Native cardiac TnI was near completely replaced in one transgenic line as assessed by in vitro phosphorylation, and this led to reduced calcium sensitivity of myofibrillar MgATPase, as expected. TnIDD22,23 mice had mildly enhanced basal systolic and diastolic function, and displayed marked augmentation of frequency-dependent inotropy and relaxation, with a peak frequency response 2-fold greater in mutants than controls (P<0.005). Increasing afterload prolonged relaxation more in nontransgenic than TnIDD22,23 (P<0.02), whereas contractile responses to afterload were similar between these strains. Isoproterenol treatment eliminated the differential force-frequency and afterload response between TnIDD22,23 and controls. In contrast to in vivo studies, isolated isometric trabeculae from nontransgenic and TnIDD22,23 mice had similar basal, isoproterenol-, and frequency-stimulated function, suggesting that muscle shortening may be important to TnI PKA effects. These results support a novel role for cardiac TnI PKA phosphorylation in the rate-dependent enhancement of systolic and diastolic function in vivo and afterload sensitivity of relaxation. These results have implications for cardiac failure in which force-frequency modulation is blunted and afterload relaxation sensitivity increased in association with diminished PKA TnI phosphorylation.
- Subjects :
- Actin Cytoskeleton metabolism
Amino Acid Substitution
Animals
Biomechanical Phenomena
Ca(2+) Mg(2+)-ATPase metabolism
Calcium pharmacology
Calcium-Binding Proteins metabolism
Cardiac Pacing, Artificial
Diastole
Isoproterenol pharmacology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle Proteins metabolism
Mutagenesis, Site-Directed
Myocardial Contraction drug effects
Myocardial Contraction physiology
Phosphorylation
Rats
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins physiology
Systole
Troponin I chemistry
Troponin I genetics
Cyclic AMP-Dependent Protein Kinases metabolism
Protein Processing, Post-Translational
Troponin I physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 94
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 14726477
- Full Text :
- https://doi.org/10.1161/01.RES.0000117307.57798.F5