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activation by NO/cGMP
1 Physiology, Alcala University, Alcala de Henares, Madrid, Spain; Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Madrid, Spain
2 Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Madrid, Spain; Nephrology, Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain
* To whom correspondence should be addressed. E-mail: sergio.frutos{at}uah.es.
cGMP is generated in endothelial cells after stimulation of soluble guanylyl cyclase (sGC) by nitric oxide (NO) or of particulate guanylyl cyclase (pGC) by natriuretic peptides (NP). We examined whether localized increases in cytosolic cGMP have distinct regulatory roles on the contraction induced by H2O2 treatment in human umbilical vein endothelial cells (HuVEC). cGMP concentrations and temporal dynamics were different upon NO stimulation of sGC or C-type NP (CNP) activation of pGC, and did not correlate with their relaxing effects measured as planar cell surface area (PCSA) after H2O2 challenge. cGMP production due to sGC stimulation was always smaller and brief than that induced by pGC stimulation with CNP, which was greater and remained elevated longer. The NO effects on cell relaxation were cGMP dependent since they were blocked by sGC inhibition with ODQ and mimicked by 8-Br-cGMP. An antagonist of the cGMP-dependent protein kinase type-I (PKG-I) also inhibited the NO-induced effects. The cell contraction induced by H2O2 produces myosin light chain (MLC) phosphorylation and NO prevented it completely whereas CNP only produced a partial inhibition. Transfection with a dominant negative form of PKG type-I
completely reversed the NO-induced effects on MLC phosphorylation while it only partially inhibited the effects due to CNP. Taken together these results demonstrate that the NO/sGC/cGMP pathway induces endothelial cell relaxation in a more efficient manner than CNP/pGC/cGMP pathway, an effect that might be related to a selective stimulation of PKG-1 by NO-derived cGMP. Consequently, stimulated PKG-I may phosphorylate important protein targets that are necessary to inhibit the endothelial contractile machinery activated by oxidative stress.
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