Abnormal Ca 2+ Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure
| Autor: | Andrew J. Lokuta, Emily F. Farrell, Héctor H. Valdivia, Robert A. Haworth, Ming Tao Jiang, Matthew R. Wolff |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Physiology Blotting Western chemistry.chemical_element Stimulation Calcium-Transporting ATPases Calcium Biology Binding Competitive Sarcoplasmic Reticulum Calcium-Transporting ATPases Tacrolimus Binding Proteins Dogs Internal medicine medicine Animals Humans Calcium Signaling Phosphorylation Calcium signaling Heart Failure Calcium metabolism Ryanodine receptor Myocardium Endoplasmic reticulum Calcium-Binding Proteins Ryanodine Receptor Calcium Release Channel Cyclic AMP-Dependent Protein Kinases Transport protein Phospholamban Disease Models Animal Sarcoplasmic Reticulum Endocrinology chemistry cardiovascular system Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 91:1015-1022 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/01.res.0000043663.08689.05 |
| Popis: | Sarcoplasmic reticulum (SR) Ca 2+ transport proteins, especially ryanodine receptors (RyR) and their accessory protein FKBP12.6, have been implicated as major players in the pathogenesis of heart failure (HF), but their role remain controversial. We used the tachycardia-induced canine model of HF and human failing hearts to investigate the density and major functional properties of RyRs, SERCA2a, and phospholamban (PLB), the main proteins regulating SR Ca 2+ transport. Intracellular Ca 2+ is likely to play a role in the contractile dysfunction of HF because the amplitude and kinetics of the [Ca 2+ ] i transient were reduced in HF. Ca 2+ uptake assays showed 44±8% reduction of V max in canine HF, and Western blots demonstrated that this reduction was due to decreased SERCA2a and PLB levels. Human HF showed a 30±5% reduction in SERCA2a, but PLB was unchanged. RyRs from canine and human HF displayed no major structural or functional differences compared with control. The P o of RyRs was the same for control and HF over the range of pCa 7 to 4. Subconductance states, which predominate in FKBP12.6-stripped RyRs, were equally frequent in control and HF channels. An antibody that recognizes phosphorylated RyRs yields equal intensity for control and HF channels. Further, phosphorylation of RyRs by PKA did not appear to change the RyR/FKBP12.6 association, suggesting minor β-adrenergic stimulation of Ca 2+ release through this mechanism. These results support a role for SR in the pathogenesis of HF, with abnormal Ca 2+ uptake, more than Ca 2+ release, contributing to the depressed and slow Ca 2+ transient characteristic of HF. |
| Databáze: | OpenAIRE |
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