RNA SEQ Analysis Indicates that the AE3 Cl − /HCO 3 − Exchanger Contributes to Active Transport-Mediated CO 2 Disposal in Heart

Loss of the AE3 Cl − /HCO 3 − 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 2 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 2 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 2 /CO 2 balance in AE3-null myocytes. Given that the myocardium is an obligate aerobic tissue and consumes large amounts of O 2 , the data suggest that loss of AE3, which has the potential to extrude CO 2 in the form of HCO 3 − , impairs O 2 /CO 2 balance in cardiac myocytes. These results support a model in which the AE3 Cl − /HCO 3 − exchanger, coupled with parallel Cl − and H + -extrusion mechanisms and extracellular carbonic anhydrase, is responsible for active transport-mediated disposal of CO 2 .