Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy

Area of Science:

• Cardiology
• Molecular Biology
• Cell Physiology

Background:

• Pressure overload leads to cardiac hypertrophy and heart failure.
• Calcium handling, specifically calcium-induced calcium release (CICR), is crucial for heart contraction but is impaired in heart failure.
• The precise molecular mechanisms underlying CICR defects during hypertrophy are not fully understood.

Purpose of the Study:

• To investigate the intermolecular coupling between L-type calcium channels (LCCs) and ryanodine receptors (RyRs) during pressure overload-induced cardiac hypertrophy.
• To determine if defects in this coupling precede or coincide with cellular dysfunction.
• To elucidate the role of junctophilin in mediating LCC-RyR interactions.

Main Methods:

• Utilized loose-patch confocal imaging in rat models of compensated (CHT) and decompensated (DHT) hypertrophy induced by aortic stenosis.
• Quantified LCC-RyR coupling parameters including latency, chance of hit, and chance of miss.
• Assessed junctophilin expression levels.

Main Results:

• Decompensated hypertrophy (DHT) exhibited prolonged LCC-RyR coupling latency and reduced coupling efficiency, termed "intermolecular failure."
• Compensated hypertrophy (CHT) also showed significant intermolecular failure, linked to decreased junctophilin expression, indicating it occurs before overt cellular changes.
• Cell-wide calcium release (spikes) desynchronized in CHT, but cellular calcium transient integrity was maintained within a "stability margin."

Conclusions:

• "Intermolecular failure" in calcium signaling is an early event in cardiac hypertrophy, preceding cellular dysfunction.
• Decreased junctophilin expression contributes to this early intermolecular failure.
• Cardiac excitation-contraction coupling maintains integrity within a stability margin, with global failure occurring only when this margin is exceeded, highlighting potential therapeutic targets.