Destabilized calcium dynamics visualized using the genetically-coded probe GCaMPJ in intact hearts of Calstabin2-null...

Area of Science:

• Cardiovascular Physiology
• Optical Imaging
• Molecular Cardiology

Background:

• Optical imaging of intracellular calcium ions (Ca2+) provides high resolution but has limitations in visualizing global Ca2+ events in intact mammalian hearts.
• Understanding whole-heart arrhythmogenesis requires sensitive macroscopic imaging tools to study Ca2+ signaling dynamics.
• Genetically encoded Ca2+ indicators (GECIs) offer potential for improved Ca2+ imaging in cardiac research.

Purpose of the Study:

• To develop and utilize a highly sensitive macroscopic imaging tool for visualizing global Ca2+ events in intact mammalian hearts.
• To investigate the role of Calstabin in modulating Ca2+ cycling and its impact on arrhythmogenesis.
• To explore the potential of pharmacological stabilization of the ryanodine receptor (RyR) complex in preventing arrhythmias.

Main Methods:

• Generated transgenic mice with cardiac-specific expression of GCaMPJ, an optimized, non-cardiotoxic Ca2+ indicator.
• Employed macroscopic optical imaging to visualize Ca2+ waves in intact hearts.
• Utilized genetic knockout and targeted protein degradation techniques to study protein function.
• Administered pharmacological agents to stabilize the ryanodine receptor (RyR) complex.

Main Results:

• Achieved macroscopic visualization of complex spiral and ripple Ca2+ waves in intact hearts using GCaMPJ.
• Established the critical role of Calstabin in modulating Ca2+ cycling within the intact heart.
• Demonstrated that pharmacological stabilization of the RyR complex prevents spatial discordance and ventricular arrhythmias.

Conclusions:

• The developed GCaMPJ-based imaging platform enables sensitive macroscopic visualization of cardiac Ca2+ dynamics.
• Calstabin plays a crucial role in regulating Ca2+ cycling and preventing arrhythmias in the intact heart.
• Pharmacological stabilization of the RyR complex is a promising strategy for managing cardiac arrhythmias.