Abstract
Diminished Ca release from the sarcoplasmic reticulum (SR) is an important
contributor to the impaired contractility of the failing heart. Despite
extensive effort, the underlying causes of abnormal SR Ca release
in heart failure (HF) remain unknown. We used a combination of simultaneous
imaging of cytosolic and SR intraluminal Ca in isolated cardiomyocytes
and recordings from single-ryanodine receptor (RyR) channels reconstituted
into lipid bilayers to investigate alterations in intracellular Ca
handling in an experimental model of chronic HF. We found that diastolic
free Ca inside the SR was dramatically reduced because of a Ca
leak across the SR membrane, mediated by spontaneous local release
events (Ca sparks), in HF myocytes. Additionally, the magnitudes
of intrastore Ca depletion signals during global and focal Ca release
events were blunted, and CaSR recovery was slowed after global
but not focal Ca release in HF myocytes. At the single-RyR level,
the sensitivity of RyRs to activation by luminal Ca was greatly enhanced,
providing a molecular mechanism for the maintained potentiation of
Ca sparks (and increased Ca leak) at reduced intra-SR Ca in HF.
This work shows that the diminished SR Ca release characteristic
of failing myocardium could be explained by increased sensitivity
of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak
and reduced intra-SR Ca.
- 16172392
- animals,
- calcium
- calcium,
- cardiac
- cardiac,
- channel,
- chronic
- disease,
- dogs,
- extramural,
- gov't,
- heart,
- low,
- muscle
- myocardium,
- myocytes,
- n.i.h.,
- non-u.s.
- output,
- p.h.s.,
- proteins,
- receptor
- release
- research
- reticulum,
- ryanodine
- sarcoplasmic
- signaling,
- support,
- u.s.
Users
Please
log in to take part in the discussion (add own reviews or comments).