Differential regulation of two types of intracellular calcium release channels during end-stage heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Human Pathophysiology

Background:

• The molecular mechanisms underlying human heart failure remain largely unknown.
• Dysregulation of calcium homeostasis is a hallmark of failing cardiac muscle.
• Intracellular calcium-release channels, including ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R), are critical for cardiac contractility.

Purpose of the Study:

• To investigate the differential regulation of cardiac ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP3R) in human heart failure.
• To elucidate the potential roles of altered calcium channel expression in the pathophysiology of heart failure.

Main Methods:

• Quantitative analysis of RyR and IP3R mRNA levels in failing human left ventricles using molecular biology techniques.
• In situ hybridization to localize RyR and IP3R mRNA expression within human cardiac myocytes.
• Assessment of relative binding site densities for IP3 and ryanodine in failing hearts.

Main Results:

• Significant downregulation of RyR mRNA by 31% (P < 0.025) in failing human left ventricles.
• Significant upregulation of IP3R mRNA by 123% (P < 0.005) in failing human left ventricles.
• Increased IP3 binding sites (~40%) relative to ryanodine binding sites in failing hearts, with both mRNAs localized to cardiac myocytes.

Conclusions:

• Cardiac intracellular calcium release channels, RyR and IP3R, are oppositely regulated in human heart failure.
• RyR downregulation may impair cardiac contractility.
• IP3R upregulation might represent a compensatory mechanism contributing to diastolic dysfunction and myocardial hypertrophy in heart failure.