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Peroxynitrite Stimulates Pulmonary Artery Endothelial and Smooth Muscle Cell Proliferation: Involvement of ERK and PKC

Peroxynitrite Stimulates Pulmonary Artery Endothelial and Smooth Muscle Cell Proliferation: Involvement of ERK and PKC

E O Agbani, P Coats, A Mills, R M Wadsworth

Pulm Pharmacol Ther. 2011 Feb;24(1):100-9.

PMID: 20851205

Abstract:

Background:
There is evidence that peroxynitrite is generated in pulmonary hypertension and we have therefore investigated whether peroxynitrite can cause proliferation of pulmonary artery cells.
Methods:
Bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC) were exposed to peroxynitrite solution or to the peroxynitrite generating compound, 3-morpholinosydnonimine (SIN-1). Vascular cell proliferation was determined by cell count and (3)H-thymidine incorporation. Protein biochemistry was by western blot analysis.
Results:
Transient exposure to peroxynitrite stimulated the proliferation of PASMC (peroxynitrite 0.2 nM-2 μM) and PAEC (peroxynitrite 0.2 μM). Peroxynitrite 0.2 μM stimulated DNA synthesis in PASMC cell by 200 ± 22% and in PAEC by 137 ± 4%. DNA synthesis in PAEC and PASMC was also stimulated by the peroxynitrite generator SIN-1 2 μM. Cell proliferation was accompanied by activation of ERK, which peaked at 15 min and remained elevated for 12 h in PASMC. However peroxynitrite at the concentrations used in this study did not activate the stress pathways p38 mitogen activated protein kinase (MAPK) or Jun N-terminal kinase (JNK). Peroxynitrite-induced proliferation and ERK phosphorylation in PASMC were abolished by the peroxynitrite scavenger ebselen 5 μM. Peroxynitrite-induced proliferation and extracellular signal-regulated kinase (ERK) phosphorylation in PASMC was prevented by selective inhibitors of MAP kinase kinase (MEK) (U0126 5 μM, PD98059 50 μM), Raf-1 (Raf-1 kinase inhibitor 10 μM), Ras (FPT II and FPT III 10 μM) and protein kinase C (PKC) (GF109203X 10 μM). Inhibition of EGF or PDGF receptor signaling using AG-1296, AG-1478 or imatinib prevented peroxynitrite-induced cell proliferation and ERK phosphorylation in PASMC.
Conclusion:
Peroxynitrite can stimulate proliferation of pulmonary artery cells, involving ERK, PKC and EGF or PDGF receptors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415499	InSolution p38 MAP Kinase Inhibitor III			Price

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