title: Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility.
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.
authors: Cardiovascular Pulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD 20892, United States. begumn@csr.nih.gov
authors: Najma
authors: N
authors: Begum
authors: Weixing
authors: W
authors: Shen
authors: Vincent
authors: V
authors: Manganiello
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D000090204:Mesothelin; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009866:Oogenesis / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007527:Isoenzymes; C000715528:Msln protein, mouse; D058987:Phosphodiesterase 3 Inhibitors; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517289:Pde3a protein, mouse; D000090204:Mesothelin