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UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

Li Wang1, Brian T Burmeister1, Keven R Johnson1

  • 1Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.

Cellular Signalling
|February 17, 2015
PubMed

Insights

Phosphodiesterase 4 (PDE4) activation by UCR1C prevents cardiomyocyte hypertrophy by inhibiting protein kinase A (PKA) signaling. This finding offers a potential therapeutic target for heart failure treatment.

Area of Science:

  • Cardiovascular Biology
  • Molecular Pharmacology
  • Cell Signaling

Background:

  • Cardiac hypertrophy is a significant risk factor for heart failure and arrhythmia.
  • Chronic beta-adrenergic receptor (β-AR) stimulation leads to cardiomyocyte hypertrophy via increased cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activation.
  • Phosphodiesterases (PDEs) regulate cAMP levels, influencing cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of PDE4 in regulating cardiomyocyte hypertrophy.
  • To identify novel regulators of PDE4 activity.
  • To explore the potential of targeting PDE4 for the prevention of maladaptive cardiac hypertrophy.

Main Methods:

  • Investigated the effects of PDE3 and PDE4 inhibition on cardiomyocyte hypertrophy.
  • Identified and characterized a novel activator of PDE4 long isoforms, termed UCR1C.
  • Examined the interaction of UCR1C with A-kinase anchoring protein (AKAP)-Lbc and its effect on PKA signaling.
  • Assessed the impact of UCR1C expression on cardiomyocyte hypertrophy induced by chronic β-AR stimulation.
  • Analyzed the effect of UCR1C on nuclear PKA activity and CREB phosphorylation.

Main Results:

  • PDE4, not PDE3, was found to be critical in regulating cardiomyocyte hypertrophy.
  • A novel sequence, UCR1C, was identified as an activator of PDE4 long isoforms.
  • UCR1C, in complex with AKAP-Lbc, decreases PKA signaling.
  • Expression of UCR1C in cardiomyocytes inhibited hypertrophy induced by chronic β-AR stimulation.
  • UCR1C attenuated hypertrophy by inhibiting nuclear PKA activity and subsequent CREB phosphorylation.

Conclusions:

  • PDE4 plays a crucial role in mediating cardiomyocyte hypertrophy.
  • UCR1C acts as a novel activator of PDE4, specifically targeting long isoforms.
  • PDE4 activation by UCR1C represents a potential therapeutic strategy for preventing maladaptive cardiac hypertrophy and associated heart failure.

Keywords:
3′,5′-cyclic monophosphate (cAMP)A-kinase anchoring protein (AKAP)Compartmentalized signalingPhosphodiesterase 4 (PDE4) activationcardiomyocyte hypertrophyprotein kinase A (PKA)

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