Abstract
Pressure overload–induced hypertrophy is a key step leading to heart failure. The Ca2+-induced Ca2+ 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 Ca2+ 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 Ca2+ release, visualized as “Ca2+ spikes,” became desynchronized, which contrasted sharply with unaltered spike integrals and whole-cell Ca2+ 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.
Highlights
In response to pressure overload, the heart produces an adaptive response in the form of cardiac hypertrophy to maintain adequate cardiac output and tissue perfusion [1,2,3]
High blood pressure induces hypertrophy, a thickening of the cardiac muscle that eventually leads to heart failure, a leading cause of morbidity and mortality
The contractile power of the heart depends in part on signaling between calcium channels on the cell membrane (L-type Ca2þ channels) and calcium release channels on a specialized calcium-regulating organelle called the sarcoplasmic reticulum
Summary
In response to pressure overload, the heart produces an adaptive response in the form of cardiac hypertrophy to maintain adequate cardiac output and tissue perfusion [1,2,3]. In the early stage of hypertrophy, cardiac contractile dysfunction is not present, and the ventricle is hemodynamically compensated. When the pressure stimuli are persistent, the heart usually undergoes functional deterioration, eventually leading to heart failure [3,4]. The heart becomes incapable of generating sufficient pumping power. To prevent the pathogenesis of heart failure, one strategy has been to stop or postpone the transition of hypertrophy from the compensated stage toward the decompensated stage [4]. Understanding the cellular and molecular mechanisms involved in cardiac hypertrophy is important for developing clinical therapies against heart failure
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