Loss of the AE3 Cl/HCO 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 (CO 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 CO 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 O/CO balance in AE3-null myocytes. Given that the myocardium is an obligate aerobic tissue and consumes large amounts of O, the data suggest that loss of AE3, which has the potential to extrude CO in the form of HCO, impairs O/CO balance in cardiac myocytes. These results support a model in which the AE3 Cl/HCO exchanger, coupled with parallel Cl and H-extrusion mechanisms and extracellular carbonic anhydrase, is responsible for active transport-mediated disposal of CO.
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