Figure 4

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).