Molecular mechanisms of nitric oxide-induced growth arrest and apoptosis in fetal pulmonary arterial smooth muscle cells

Stephen Wedgwood, Stephen Matthew Black

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Superoxide plays an important role in pulmonary arterial smooth muscle cell (SMC) proliferation and survival. The rapid reaction between superoxide and nitric oxide (NO) to form peroxynitrite suggests that endothelium-derived NO may influence adjacent SMC growth. To investigate this possibility, we determined the dose-dependent effects of NO on the proliferation and viability of pulmonary arterial SMC isolated from fetal lambs (FPASMC). Using fluorescence microscopy we found a dose-dependent decrease in superoxide levels in FPASMC treated with the NO donor spermine NONOate. This was associated with an increase in peroxynitrite-mediated protein nitration. At doses between 50 and 250 μM, spermine NONOate attenuated serum-induced FPASMC proliferation resulting in a G0/G1 cell cycle arrest. This process involved a decrease in levels of cyclin A and an increase in the nuclear localization of p21 and p27. Furthermore, 500 μM spermine NONOate decreased viable cell number by inducing programmed cell death: FPASMC treated with 500 μM spermine NONOate displayed a loss of mitochondrial membrane potential, followed by caspase activation and DNA fragmentation. These data suggest that NO inhibits superoxide-induced proliferation of FPASMC and at higher doses induces apoptosis. NO donors may therefore prove to be useful therapeutic tools to treat diseases resulting from excessive proliferation of vascular smooth muscle.

Original languageEnglish (US)
Pages (from-to)201-210
Number of pages10
JournalNitric Oxide - Biology and Chemistry
Volume9
Issue number4
DOIs
StatePublished - Dec 1 2003

Fingerprint

Superoxides
Smooth Muscle Myocytes
Muscle
Nitric Oxide
Cells
Apoptosis
Lung
Peroxynitrous Acid
Nitric Oxide Donors
Growth
G1 Phase Cell Cycle Checkpoints
Nitration
Cyclin A
Mitochondrial Membrane Potential
Fluorescence microscopy
Cell proliferation
Cell growth
DNA Fragmentation
Cell death
Caspases

Keywords

  • Apoptosis
  • G/G growth arrest
  • Nitric oxide
  • Superoxide
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Cite this

Molecular mechanisms of nitric oxide-induced growth arrest and apoptosis in fetal pulmonary arterial smooth muscle cells. / Wedgwood, Stephen; Black, Stephen Matthew.

In: Nitric Oxide - Biology and Chemistry, Vol. 9, No. 4, 01.12.2003, p. 201-210.

Research output: Contribution to journalArticle

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