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Am J Physiol Cell Physiol 279: C225-C235, 2000;
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Vol. 279, Issue 1, C225-C235, July 2000

NO regulates PDGF-induced activation of PKB but not ERK in A7r5 cells: implications for vascular growth arrest

Lakshman Sandirasegarane, Roger Charles, Nicole Bourbon, and Mark Kester

Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

In addition to the well-documented role of nitric oxide (NO) as a vasodilator, NO has also been implicated in vascular smooth muscle cell (VSMC) growth arrest. Signaling mechanisms responsible for growth factor receptor-mediated VSMC proliferation include the extracellular signal-regulated kinase (ERK) and possibly the protein kinase B (PKB) cascade. Thus the present study was designed to test the hypothesis that, in A7r5 vascular smooth muscle-derived cells, platelet-derived growth factor (PDGF)-induced activation of either ERK or PKB is regulated by NO, which then modulates cellular proliferation and/or apoptosis. PKB-alpha was the predominant isoform of PKB expressed in A7r5 cells and was also expressed in rabbit carotid arteries and aortae. Phosphorylation of PKB-alpha and ERK induced by PDGF-BB was maximal within 5-15 min in A7r5 cells. Preincubation of A7r5 cells with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) resulted in a biphasic regulation of PDGF-stimulated PKB-alpha phosphorylation and bioactivity. Acute exposure to SNAP significantly augmented PDGF-induced activation of PKB-alpha , whereas prolonged incubation led to a marked diminution in PDGF-induced activation of PKB-alpha . In contrast, SNAP did not affect PDGF-induced activation of ERK at any time point. The cGMP-independent effects of SNAP on PDGF-induced activation of PKB-alpha were established with the use of an inhibitor of soluble guanylyl cyclase, ODQ, as well as a cell-permeable analog of cGMP, 8-bromo-cGMP. Prolonged treatment of A7r5 cells with SNAP led to a significant decrease in DNA synthesis without an appreciable increase in apoptosis. These data suggest that, after prolonged exposure to SNAP, NO selectively attenuates PDGF-induced increase in PKB-alpha activation, which in turn may contribute to diminished VSMC proliferation by mechanisms involving growth arrest but not apoptosis.

protein kinase B; extracellular signal-regulated kinase; nitric oxide; growth factors; proliferation; platelet-derived growth factor; vascular smooth muscle cell


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