Abstract
Abnormal release of Ca from sarcoplasmic reticulum (SR) via the cardiac
ryanodine receptor (RyR2) may contribute to contractile dysfunction
and arrhythmogenesis in heart failure (HF). We previously demonstrated
decreased Ca transient amplitude and SR Ca load associated with increased
Na/Ca exchanger expression and enhanced diastolic SR Ca leak in an
arrhythmogenic rabbit model of nonischemic HF. Here we assessed expression
and phosphorylation status of key Ca handling proteins and measured
SR Ca leak in control and HF rabbit myocytes. With HF, expression
of RyR2 and FK-506 binding protein 12.6 (FKBP12.6) were reduced,
whereas inositol trisphosphate receptor (type 2) and Ca/calmodulin-dependent
protein kinase II (CaMKII) expression were increased 50\% to 100\%.
The RyR2 complex included more CaMKII (which was more activated)
but less calmodulin, FKBP12.6, and phosphatases 1 and 2A. The RyR2
was more highly phosphorylated by both protein kinase A (PKA) and
CaMKII. Total phospholamban phosphorylation was unaltered, although
it was reduced at the PKA site and increased at the CaMKII site.
SR Ca leak in intact HF myocytes (which is higher than in control)
was reduced by inhibition of CaMKII but was unaltered by PKA inhibition.
CaMKII inhibition also increased SR Ca content in HF myocytes. Our
results suggest that CaMKII-dependent phosphorylation of RyR2 is
involved in enhanced SR diastolic Ca leak and reduced SR Ca load
in HF, and may thus contribute to arrhythmias and contractile dysfunction
in HF.
- 16339492
- 1a,
- amp-dependent
- and
- animals,
- arrhythmia,
- atpase,
- benzylamines,
- binding
- calcium
- calcium,
- calcium-binding
- cardiac,
- channel,
- channels,
- congestive,
- cyclic
- cytoplasmic
- dependent
- dulin
- echocardiography,
- extramural,
- failure,
- heart
- inase,
- k,
- kinases,
- myocytes,
- n.i.h.,
- nuclear,
- phosphorylation,
- protein
- proteins,
- rabbits,
- receptor
- receptors,
- release
- research
- reticulum,
- ryanodine
- sarcoplasmic
- sulfonamides,
- support,
- tacrolimus
- {c}a$^{2+}$-calmo,
- {c}a$^{2+}$-transporting
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