title: Carbonic anhydrase II promotes cardiomyocyte hypertrophy.
abstract: Pathological cardiac hypertrophy, the maladaptive remodelling of the myocardium, often progresses to heart failure. The sodium-proton exchanger (NHE1) and chloride-bicarbonate exchanger (AE3) have been implicated as important in the hypertrophic cascade. Carbonic anhydrase II (CAII) provides substrates for these transporters (protons and bicarbonate, respectively). CAII physically interacts with NHE1 and AE3, enhancing their respective ion transport activities by increasing the concentration of substrate at their transport sites. Earlier studies found that a broad-spectrum carbonic anhydrase inhibitor prevented cardiomyocyte hypertrophy (CH), suggesting that carbonic anhydrase is important in the development of hypertrophy. Here we investigated whether cytosolic CAII was the CA isoform involved in hypertrophy. Neonatal rat ventricular myocytes (NRVMs) were transduced with recombinant adenoviral constructs to over-express wild-type or catalytically inactive CAII (CAII-V143Y). Over-expression of wild-type CAII in NRVMs did not affect CH development. In contrast, CAII-V143Y over-expression suppressed the response to hypertrophic stimuli, suggesting that CAII-V143Y behaves in a dominant negative fashion over endogenous CAII to suppress hypertrophy. We also examined CAII-deficient (Car2) mice, whose hearts exhibit physiological hypertrophy without any decrease in cardiac function. Moreover, cardiomyocytes from Car2 mice do not respond to prohypertrophic stimulation. Together, these findings support a role of CAII in promoting CH.
authors.affiliation: Membrane Protein Disease Research Group, Department of Biochemistry, School of Translational Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Brittany F
authors.initials: BF
authors.lastname: Brown
authors.forename: Anita
authors.initials: A
authors.lastname: Quon
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
mesh_terms: D000818:Animals; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D010656:Phenylephrine / Q000378:metabolism; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D017923:Sodium-Hydrogen Exchangers; D010656:Phenylephrine; D024402:Carbonic Anhydrase II