期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 299, 期 4, 页码 H1235-H1241出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00513.2010
关键词
guanosine 3 ',5 '-cyclic monophosphate; redox; vasodilator mechanisms
资金
- National Heart, Lung, and Blood Institute [HL-31069, HL-43023, HL-66331]
Neo BH, Kandhi S, Wolin MS. Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide. Am J Physiol Heart Circ Physiol 299: H1235-H1241, 2010. First published August 13, 2010; doi:10.1152/ajpheart.00513.2010.-We have previously provided evidence that hydrogen peroxide (H2O2) stimulates soluble guanylate cyclase (sGC) under conditions where it relaxes isolated endothelium-removed bovine pulmonary arteries (BPAs). Since it was recently reported that H2O2 induces coronary vasorelaxation associated with a nitric oxide/cGMP-independent thiol oxidation/subunit dimerization-elicited activation of protein kinase G (PKG), we investigated whether this mechanism participates in the relaxation of BPAs to H2O2. BPAs precontracted with serotonin (incubated under hypoxia to lower endogenous H2O2) were exposed to increasing concentrations of H2O2. It was observed that 0.1-1 mM H2O2 caused increased PKG dimerization and relaxation. These responses were associated with increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at the serine-239 site known to be mediated by PKG. Treatment of BPAs with 1 mM DTT attenuated PKG dimerization, VASP phosphorylation, and relaxation to H2O2. An organoid culture of BPAs for 48 h with 10 mu M 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), a heme oxidant inhibitor of sGC activation, depleted sGC expression by 85%, associated with a 67% attenuation of VASP phosphorylation and 48% inhibition of relaxation elicited by 100 mu M H2O2. Thus both a sGC activation/cGMP-dependent and a thiol oxidation subunit dimerization/cGMP-independent activation of PKG appear to contribute to the relaxation of BPAs elicited by H2O2.
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