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Published on: May 15, 2011
Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart
Bernardo V Alvarez1, Anita L Quon, John Mullen
1Department of Biochemistry, and Membrane Protein Disease Research Group, University of Alberta, Edmonton, AB, Canada.
Insights
Increased carbonic anhydrase (CA) expression, specifically CAII and CAIV, is found in hypertrophied human hearts. This suggests CA may be a prognostic marker for cardiac hypertrophy and heart failure progression.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Molecular Biology
Background:
- Carbonic anhydrase (CA) enzymes regulate cellular pH by catalyzing CO2 hydration.
- pH regulation is implicated in cardiac hypertrophy (CH), a hallmark of heart failure.
- CA activity activates Na+/H+ exchange (NHE), a pro-hypertrophic pathway.
Purpose of the Study:
- To investigate if hypertrophied human hearts exhibit altered expression of carbonic anhydrase (CA) isoforms.
- To explore the role of CA in the progression of human heart failure.
Main Methods:
- Quantitative real-time PCR was used to measure mRNA levels of CA isoforms, ANP, and BNP in human ventricular biopsies.
- Protein expression of CAII, CAIV, and ANP was assessed in hypertrophied/dilated ventricles.
- Ventricular samples were obtained from patients undergoing cardiac surgery (CS) and heart transplantation (HT).
Main Results:
- Hypertrophied ventricles showed increased mRNA and protein expression of CAII and CAIV.
- Markers of cardiac hypertrophy, atrial and brain natriuretic peptide (ANP and BNP), were also elevated.
- Expression levels of CAII, CAIV, ANP, and BNP increased in failing hearts.
Conclusions:
- Increased expression of CAII and CAIV in hypertrophied human hearts suggests a role in cardiac hypertrophy.
- Elevated carbonic anhydrase expression may serve as a prognostic molecular marker for cardiac hypertrophy.
- These findings align with in vitro data showing CA inhibition prevents and reverts CH.
Background:
Carbonic anhydrase enzymes (CA) catalyze the reversible hydration of carbon dioxide to bicarbonate in mammalian cells. Trans-membrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation. A body of evidence implicates pH-regulatory processes in the hypertrophic growth pathway characteristic of hearts as they fail. In particular, Na+/H+ exchange (NHE) activation is pro-hypertrophic and CA activity activates NHE. Recently Cardrase (6-ethoxyzolamide), a CA inhibitor, was found to prevent and revert agonist-stimulated cardiac hypertrophy (CH) in cultured cardiomyocytes. Our goal thus was to determine whether hypertrophied human hearts have altered expression of CA isoforms.
Methods:
We measured CA expression in hypertrophied human hearts to begin to examine the role of carbonic anhydrase in progression of human heart failure. Ventricular biopsies were obtained from patients undergoing cardiac surgery (CS, n = 14), or heart transplantation (HT, n = 13). CS patients presented mild/moderate concentric left ventricular hypertrophy and normal right ventricles, with preserved ventricular function; ejection fractions were ~60%. Conversely, HT patients with failing hearts presented CH or ventricular dilation accompanied by ventricular dysfunction and EF values of 20%. Non-hypertrophic, non-dilated ventricular samples served as controls.
Results:
Expression of atrial and brain natriuretic peptide (ANP and BNP) were markers of CH. Hypertrophic ventricles presented increased expression of CAII, CAIV, ANP, and BNP, mRNA levels, which increased in failing hearts, measured by quantitative real-time PCR. CAII, CAIV, and ANP protein expression also increased approximately two-fold in hypertrophic/dilated ventricles.
Conclusions:
These results, combined with in vitro data that CA inhibition prevents and reverts CH, suggest that increased carbonic anhydrase expression is a prognostic molecular marker of cardiac hypertrophy.
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