KATP channel dependent heart multiome atlas

Plasmalemmal ATP sensitive potassium (K-ATP) channels are recognized metabolic sensors, yet their cellular reach is less well understood. Here, transgenic Kir6.2 null hearts devoid of the K-ATP channel pore underwent multiomics surveillance and systems interrogation versus wildtype counterparts. Despite maintained organ performance, the knockout proteome deviated beyond a discrete loss of constitutive K-ATP channel subunits. Multidimensional nano-flow liquid chromatography tandem mass spectrometry resolved 111 differentially expressed proteins and their expanded network neighborhood, dominated by metabolic process engagement. Independent multimodal chemometric gas and liquid chromatography mass spectrometry unveiled differential expression of over one quarter of measured metabolites discriminating the Kir6.2 deficient heart metabolome. Supervised class analogy ranking and unsupervised enrichment analysis prioritized nicotinamide adenine dinucleotide (NAD(+)), affirmed by extensive overrepresentation of NAD(+) associated circuitry. The remodeled metabolome and proteome revealed functional convergence and an integrated signature of disease susceptibility. Deciphered cardiac patterns were traceable in the corresponding plasma metabolome, with tissue concordant plasma changes offering surrogate metabolite markers of myocardial latent vulnerability. Thus, Kir6.2 deficit precipitates multiome reorganization, mapping a comprehensive atlas of the K-ATP channel dependent landscape.

Automated summary

This study used multiomics surveillance and systems interrogation to study the cellular impact of Kir6.2 deficiency in the heart. The results showed that despite normal organ performance, the knockout hearts exhibited altered proteome and metabolome profiles, indicating that Kir6.2 deficiency can lead to metabolic reorganization and disease susceptibility.