Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy.
Pressure overload-induced hypertrophy is a key step leading to heart failure. The Ca(2+)-induced Ca(2+) release (CICR) process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive. To examine the intermolecular aspects of CICR during hypertrophy, we utilized loose-patch confocal imaging to visualize the signaling between a single L-type Ca(2+) channel (LCC) and ryanodine receptors (RyRs) in aortic stenosis rat models of compensated (CHT) and decompensated (DHT) hypertrophy. We found that the LCC-RyR intermolecular coupling showed a 49% prolongation in coupling latency, a 47% decrease in chance of hit, and a 72% increase in chance of miss in DHT, demonstrating a state of "intermolecular failure." Unexpectedly, these modifications also occurred robustly in CHT due at least partially to decreased expression of junctophilin, indicating that intermolecular failure occurs prior to cellular manifestations. As a result, cell-wide Ca(2+) release, visualized as "Ca(2+) spikes," became desynchronized, which contrasted sharply with unaltered spike integrals and whole-cell Ca(2+) transients in CHT. These data suggested that, within a certain limit, termed the "stability margin," mild intermolecular failure does not damage the cellular integrity of excitation-contraction coupling. Only when the modification steps beyond the stability margin does global failure occur. The discovery of "hidden" intermolecular failure in CHT has important clinical implications.
Xu
Ming
M
State Key Lab of Biomembrane and Membrane Biotechnology, Ministry of Education Key Lab of Molecular Cardiovascular Sciences and Institute of Vascular Medicine, Third Hospital, College of Life Sciences, Peking University, Beijing, China.
Zhou
Peng
P
Xu
Shi-Ming
SM
Liu
Yin
Y
Feng
Xinheng
X
Bai
Shu-Hua
SH
Bai
Yan
Y
Hao
Xue-Mei
XM
Han
Qide
Q
Zhang
Youyi
Y
Wang
Shi-Qiang
SQ
D000818:Animals; D001011:Aorta / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology; D018613:Microscopy, Confocal; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel