RNA SEQ Analysis Indicates that the AE3 Cl^-/HCO₃^- Exchanger Contributes to Active Transport-Mediated CO₂ Disposal in Heart.

Loss of the AE3 Cl^-/HCO₃^- exchanger (Slc4a3) in mice causes an impaired cardiac force-frequency response and heart failure under some conditions but the mechanisms are not known. To better understand the functions of AE3, we performed RNA Seq analysis of AE3-null and wild-type mouse hearts and evaluated the data with respect to three hypotheses (CO₂ disposal, facilitation of Na⁺-loading, and recovery from an alkaline load) that have been proposed for its physiological functions. Gene Ontology and PubMatrix analyses of differentially expressed genes revealed a hypoxia response and changes in vasodilation and angiogenesis genes that strongly support the CO₂ disposal hypothesis. Differential expression of energy metabolism genes, which indicated increased glucose utilization and decreased fatty acid utilization, were consistent with adaptive responses to perturbations of O₂/CO₂ balance in AE3-null myocytes. Given that the myocardium is an obligate aerobic tissue and consumes large amounts of O₂, the data suggest that loss of AE3, which has the potential to extrude CO₂ in the form of HCO₃^-, impairs O₂/CO₂ balance in cardiac myocytes. These results support a model in which the AE3 Cl^-/HCO₃^- exchanger, coupled with parallel Cl^- and H⁺-extrusion mechanisms and extracellular carbonic anhydrase, is responsible for active transport-mediated disposal of CO₂.

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