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Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy

Bernardo V Alvarez1, Danielle E Johnson, Daniel Sowah

  • 1Department of Physiology, Membrane Protein Research Group, University of Alberta, Edmonton, Canada T6G2H7.

The Journal of Physiology
|November 25, 2006
PubMed

Insights

Carbonic anhydrase (CA) plays a key role in cardiac hypertrophy. Inhibiting CA with 6-ethoxyzolamide (ETZ) effectively prevents and reverses cardiomyocyte growth, offering a potential therapeutic strategy for heart failure.

Area of Science:

  • Cardiology
  • Biochemistry
  • Molecular Biology

Background:

  • Cardiac hypertrophy, an enlargement of heart muscle cells, is a major driver of heart failure progression.
  • The plasma membrane Na+-H+ exchanger (NHE1) and Cl- -HCO3- exchanger (AE3) are critical in the hypertrophic cascade.
  • Carbonic anhydrase (CA) binds to NHE1 and AE3, activating their transport functions by supplying essential substrates.

Purpose of the Study:

  • To investigate the role of carbonic anhydrase (CA) activity in mediating cardiac myocyte hypertrophy.
  • To evaluate the therapeutic potential of CA inhibition in mitigating the hypertrophic phenotype.

Main Methods:

  • Primary cultures of neonatal and adult rodent cardiomyocytes were used.
  • Phenylephrine (PE) and angiotensin II were employed to induce hypertrophy.
  • The membrane-permeant CA inhibitor 6-ethoxyzolamide (ETZ) was administered to assess its effects on cell size, hypertrophic markers, and ion exchanger activity.
  • Calcium (Ca2+) transient frequency was measured in response to PE treatment.

Main Results:

  • PE treatment significantly increased cardiomyocyte size and atrial natriuretic factor mRNA expression in neonatal rat cardiomyocytes.
  • Angiotensin II or PE also induced hypertrophy in adult cardiomyocytes.
  • Increased expression of cytosolic CAII and membrane-anchored CAIV proteins was observed.
  • ETZ demonstrated concentration-dependent prevention and reversal of PE-induced hypertrophy in neonatal cells (IC50=18 µM) and prevented hypertrophy in adult cells.
  • ETZ inhibited NHE1 and AE3 activity with EC50 values of 1.2 µM and 2.7 µM, respectively.
  • PE-induced abnormalities in cardiomyocyte Ca2+ handling were completely prevented by ETZ.

Conclusions:

  • Carbonic anhydrase (CA) plays a significant and novel role in mediating cardiac myocyte hypertrophic responses.
  • Inhibition of CA activity effectively mitigates cardiac hypertrophy and associated calcium handling abnormalities.
  • Targeting CA represents a promising therapeutic strategy for managing heart failure progression driven by cardiac hypertrophy.

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