title: Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy.
abstract: Hypertrophic cardiomyocyte growth contributes substantially to the progression of heart failure. Activation of the plasma membrane Na+-H+ exchanger (NHE1) and Cl- -HCO3- exchanger (AE3) has emerged as a central point in the hypertrophic cascade. Both NHE1 and AE3 bind carbonic anhydrase (CA), which activates their transport flux, by providing H+ and HCO3-, their respective transport substrates. We examined the contribution of CA activity to the hypertrophic response of cultured neonatal and adult rodent cardiomyocytes. Phenylephrine (PE) increased cell size by 37 +/- 2% and increased expression of the hypertrophic marker, atrial natriuretic factor mRNA, twofold in cultured neonatal rat cardiomyocytes. Cell size was also increased in adult cardiomyocytes subjected to angiotensin II or PE treatment. These effects were associated with increased expression of cytosolic CAII protein and the membrane-anchored isoform, CAIV. The membrane-permeant CA inhibitor, 6-ethoxyzolamide (ETZ), both prevented and reversed PE-induced hypertrophy in a concentration-dependent manner in neonate cardiomyocytes (IC50=18 microm). ETZ and the related CA inhibitor methazolamide prevented hypertrophy in adult cardiomyocytes. In addition, ETZ inhibited transport activity of NHE1 and the AE isoform, AE3, with respective EC50 values of 1.2 +/- 0.3 microm and 2.7 +/- 0.3 microm. PE significantly increased neonatal cardiomyocyte Ca2+ transient frequency from 0.33 +/- 0.4 Hz to 0.77 +/- 0.04 Hz following 24 h treatment; these Ca2+ -handling abnormalities were completely prevented by ETZ (0.28 +/- 0.07 Hz). Our study demonstrates a novel role for CA in mediating the hypertrophic response of cardiac myocytes to PE and suggests that CA inhibition represents an effective therapeutic approach towards mitigation of the hypertrophic phenotype.
authors.affiliation: Department of Physiology, Membrane Protein Research Group, University of Alberta, Edmonton, Canada T6G2H7.
authors.forename: Bernardo V
authors.initials: BV
authors.lastname: Alvarez
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Daniel
authors.initials: D
authors.lastname: Sowah
authors.forename: Daniel
authors.initials: D
authors.lastname: Soliman
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
mesh_terms: D000367:Age Factors; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D005016:Ethoxzolamide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000076988:Sulfate Transporters; D014162:Transfection; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D027963:Chloride-Bicarbonate Antiporters; D026901:Membrane Transport Proteins; C439529:SLC26A6 protein, human; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; D002118:Calcium; D005016:Ethoxzolamide