Integrative model presenting possible pro-hypertrophic action of carbonic anhydrases in cardiomyocytes. (1) Pro-hypertrophic agonists, including phenylephrine (Phe), Angiotensin II (AngII) and endothelin I (ET) all act upon G-protein coupled receptors (GPCR). (2) In turn protein kinase C (PKC) is activated. (3) PKC directly stimulates AE3 and indirectly stimulates NHE1, via mitogen-activated protein kinase (MAPK). (4) Cl-/HCO3
- exchange and Na+/H+ exchange by AE3 and NHE1, respectively, are stimulated by the catalytic activity of CAII, CAIV and CAXIV. CAII provides substrate HCO3
- and H+ for efflux respectively by AE3 and NHE1. CAXIV (anchored to the extracellular surface via a transmembrane segment) and CAIV (anchored to the extracellular surface via a glycosylphosphatidyl inositol linkage) consume effluxed HCO3
- to maximize the size of the transmembrane HCO3
- gradient, activating AE3. Combined activation of AE3 and NHE1 accumulates Na+ cytosolically, without effect on pH [4, 9, 32, 33]. (5) This rise in cytosolic Na+ compromises or reverses the ability the Na+/Ca2+ exchanger (NCX), which normally effluxes Ca2+, driven by the transmembrane Na+ gradient. (6) Intracellular Ca++ thus rises, which activates calcineurin. (7) A major target of calcineurin is the transcription factor, NFAT, which regulates transcription of a set of genes. Here we found that expression of CAIV and CAII in diseased human hearts increased as heart failure progressed (double-headed red arrows).