Sodium accumulation in SERCA knockout-induced heart failure.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Computational Biology

Background:

• Decreased sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) function severely impairs cardiomyocyte systolic and diastolic functions.
• Cardiomyocyte-specific Serca2 gene deletion (SERCA2 KO) in mice leads to end-stage heart failure, associated with elevated intracellular sodium ([Na(+)](i)) and acidosis.

Purpose of the Study:

• To investigate the underlying changes in Ca(2+) dynamics and metabolic homeostasis in SERCA2 knockout mice.
• To develop data-driven mathematical models of Ca(2+) dynamics in ventricular myocytes of control and SERCA2 KO mice at different time points.

Main Methods:

• Development of data-driven mathematical models simulating Ca(2+) dynamics.
• Analysis of ventricular myocytes from control, 4-week, and 7-week SERCA2 knockout mice.

Main Results:

• The 7-week SERCA2 KO model demonstrated elevated [Na(+)](i) due to increased Na(+) influx via Na(+)/Ca(2+) exchanger (NCX) and Na(+)/H(+) exchanger.
• Intracellular acidosis exacerbated Na(+)/H(+) exchanger activity.
• NCX upregulation in 7-week KO mice led to increased ATP consumption for ion transport, contributing to metabolic compromise.

Conclusions:

• Sodium accumulation in SERCA2 KO hearts, driven by NCX upregulation and acidosis, plays a critical role in heart failure development.
• A reinforcing cycle involving ATP imbalance, compromised metabolism, decreased intracellular pH, and further [Na(+)](i) elevation is implicated in heart failure pathogenesis.