Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

Curr Opin Pharmacol. 2011 Dec;11(6):725-9. doi: 10.1016/j.coph.2011.10.006. Epub 2011 Nov 1.

Abstract

Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G₀-G₁ phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G₂/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G₂/M transition.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / metabolism
  • Cell Cycle* / drug effects
  • Cell Proliferation / drug effects
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / physiology
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Female
  • Humans
  • Infertility, Female / drug therapy*
  • Infertility, Female / enzymology
  • Infertility, Female / metabolism
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Mesothelin
  • Mice
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / metabolism
  • Oocytes / drug effects
  • Oocytes / enzymology*
  • Oocytes / metabolism
  • Oogenesis / drug effects
  • Phosphodiesterase 3 Inhibitors / pharmacology*
  • Phosphodiesterase 3 Inhibitors / therapeutic use
  • Signal Transduction / drug effects

Substances

  • Isoenzymes
  • Msln protein, mouse
  • Phosphodiesterase 3 Inhibitors
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • PDE3A protein, human
  • Pde3a protein, mouse
  • Mesothelin