K_ATP channel dependent heart multiome atlas

Area of Science:

• Cardiovascular Biology
• Metabolomics
• Proteomics

Background:

• Plasmalemmal ATP-sensitive potassium (K_ATP) channels are known metabolic sensors.
• The full cellular and molecular impact of K_ATP channel dysfunction remains incompletely understood.

Purpose of the Study:

• To comprehensively investigate the multiomic consequences of K_ATP channel deficiency in the heart.
• To identify molecular signatures and potential biomarkers associated with Kir6.2 loss.

Main Methods:

• Utilized transgenic Kir6.2 null hearts and wildtype controls for multiomics analysis.
• Employed multi-dimensional nano-flow liquid chromatography tandem mass spectrometry for proteomic profiling.
• Applied multimodal chemometric gas and liquid chromatography mass spectrometry for metabolomic profiling.
• Integrated systems interrogation and network analysis.

Main Results:

• Kir6.2 deficiency led to significant proteomic (111 differentially expressed proteins) and metabolomic alterations beyond the loss of channel subunits.
• Metabolic processes and nicotinamide adenine dinucleotide (NAD+) pathways were prominently affected.
• Cardiac multiomic remodeling showed functional convergence and suggested disease susceptibility.
• Observed cardiac metabolic changes were mirrored in the plasma, identifying potential surrogate biomarkers.

Conclusions:

• Kir6.2 deficit induces a widespread reorganization of the cardiac proteome and metabolome.
• The study provides a detailed atlas of the K_ATP channel-dependent molecular landscape in the heart.
• Plasma metabolite profiles may serve as non-invasive indicators of myocardial vulnerability due to K_ATP channel dysfunction.