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Published on: April 8, 2013
Reduction in interaction between cGMP and cAMP in dog ventricular myocytes with hypertrophic failure
Qihang Zhang1, Michael Lazar, Bruno Molino
1Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, CN-19, New Brunswick, NJ 08903-0019, USA.
Insights
Cardiac myocytes in failing hearts show impaired interaction between cyclic GMP (cGMP) and cyclic AMP (cAMP) signaling pathways. While cGMP signaling is preserved, its crosstalk with cAMP is disrupted in hypertrophic failure, impacting myocyte function.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cellular Signaling
Background:
- Cardiac hypertrophy and failure are associated with depressed baseline function and signal transduction.
- The roles of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) signaling in cardiac function are critical.
- Understanding the interaction between cGMP and cAMP pathways in failing hearts is essential for therapeutic development.
Purpose of the Study:
- To investigate the hypothesis that the effects of cGMP and its interaction with cAMP are reduced in cardiac myocytes from hypertrophic failing hearts.
- To compare the functional responses to cGMP and its modulation by phosphodiesterase inhibitors in myocytes from control, hypertrophied, and failing hearts.
- To elucidate the status of cGMP and cAMP signaling crosstalk in the context of cardiac dysfunction.
Main Methods:
- Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis (hypertrophy), and dogs with pacing-induced hypertrophic failure.
- Myocyte function was assessed using a video edge detector, measuring cell shortening and relaxation rates.
- Cells were treated with 8-bromo-cGMP, phosphodiesterase inhibitors (EHNA for PDE2, milrinone for PDE3), and combinations thereof to evaluate signaling pathway interactions and intracellular cAMP levels.
Main Results:
- Failing myocytes exhibited significantly reduced baseline contractility (Rmax: 53.2 +/- 6.4 mum/s) compared to control (95.3 +/- 17.3 mum/s) and hypertrophy (88.2 +/- 5.5 mum/s) groups.
- 8-Bromo-cGMP dose-dependently reduced myocyte function across all groups.
- While EHNA and milrinone mitigated cGMP's negative effects in control and hypertrophy, they failed to do so in failing myocytes, despite increasing intracellular cAMP in all groups.
Conclusions:
- The cGMP signaling pathway itself appears preserved in hypertrophic failing cardiac myocytes.
- The interaction and crosstalk between the cGMP and cAMP signaling pathways are significantly impaired in failing cardiac myocytes.
- This impaired crosstalk may contribute to the depressed myocyte function observed in hypertrophic heart failure.
Abstract:
Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10(-7), 10(-6), and 10(-5) M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE(2)) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE(3) inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (R(max)) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (R(max): control dogs, 95.3 +/- 17.3; hypertrophy dogs, 88.2 +/- 5.5; failure dogs, 53.2 +/- 6.4 mum/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10(-6) M) and milrinone (10(-6) M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (R(max) for control dogs: cGMP, -46%; +EHNA, -21%; +milrinone, -19%; for hypertrophy dogs: cGMP, -40%; +EHNA, -13%; +milrinone, -20%; for failure dogs: cGMP, -40%; +EHNA, -29%; +milrinone, -32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.
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