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

David J. Nagel, Toru Aizawa, Kye Im Jeon, Weimin Liu, Amy Mohan, Heng Wei, Joseph M. Miano, Vincent A. Florio, Pingjin Gao, Vyacheslav A. Korshunov, Bradford C. Berk, Chen Yan

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)777-784
Number of pages8
JournalCirculation research
Volume98
Issue number6
DOIs
StatePublished - Mar 2006

Keywords

  • Apoptosis
  • Growth
  • PDE
  • Smooth muscle cell
  • Vascular injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Nagel, D. J., Aizawa, T., Jeon, K. I., Liu, W., Mohan, A., Wei, H., Miano, J. M., Florio, V. A., Gao, P., Korshunov, V. A., Berk, B. C., & Yan, C. (2006). Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circulation research, 98(6), 777-784. https://doi.org/10.1161/01.RES.0000215576.27615.fd