RGD Reference Report - Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. - Rat Genome Database

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Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival.

Authors: Nagel, DJ  Aizawa, T  Jeon, KI  Liu, W  Mohan, A  Wei, H  Miano, JM  Florio, VA  Gao, P  Korshunov, VA  Berk, BC  Yan, C 
Citation: Nagel DJ, etal., Circ Res. 2006 Mar 31;98(6):777-84. Epub 2006 Mar 2.
RGD ID: 2312521
Pubmed: PMID:16514069   (View Abstract at PubMed)
PMCID: PMC4114760   (View Article at PubMed Central)
DOI: DOI:10.1161/01.RES.0000215576.27615.fd   (Journal Full-text)

In response to biological and mechanical injury, or in vitro culturing, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a differentiated "contractile" phenotype to a dedifferentiated "synthetic" one. This results in the capacity to proliferate, migrate, and produce extracellular matrix proteins, thus contributing to neointimal formation. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP or cGMP, are critical in the homeostasis of cyclic nucleotides that regulate VSMC growth. Here, we demonstrate that PDE1A, a Ca2+-calmodulin-stimulated PDE preferentially hydrolyzing cGMP, is predominantly cytoplasmic in medial "contractile" VSMCs but is nuclear in neointimal "synthetic" VSMCs. Using primary VSMCs, we show that cytoplasmic and nuclear PDE1A were associated with a contractile marker (SM-calponin) and a growth marker (Ki-67), respectively. This suggests that cytoplasmic PDE1A is associated with the "contractile" phenotype, whereas nuclear PDE1A is with the "synthetic" phenotype. To determine the role of nuclear PDE1A, we examined the effects loss-of-PDE1A function on subcultured VSMC growth and survival using PDE1A RNA interference and pharmacological inhibition. Reducing PDE1A function significantly attenuated VSMC growth by decreasing proliferation via G1 arrest and inducing apoptosis. Inhibiting PDE1A also led to intracellular cGMP elevation, p27Kip1 upregulation, cyclin D1 downregulation, and p53 activation. We further demonstrated that in subcultured VSMCs redifferentiated by growth on collagen gels, cytoplasmic PDE1A regulates myosin light chain phosphorylation with little effect on apoptosis, whereas inhibiting nuclear PDE1A has the opposite effects. These suggest that nuclear PDE1A is important in VSMC growth and survival and may contribute to the neointima formation in atherosclerosis and restenosis.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cGMP catabolic process  IMP 2312521 RGD 
regulation of smooth muscle cell apoptotic process  IMP 2312521 RGD 
regulation of smooth muscle cell proliferation  IMP 2312521 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity  IMP 2312521 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pde1a  (phosphodiesterase 1A)


Additional Information