Effect of hypercholesterolemia and of oxidative stress on the nitric oxide-cGMP pathway.
Soluble guanylyl cyclase (sGC) is a key enzyme of the NO-cGMP pathway which is believed to mediate vasoprotective actions. In cardiovascular diseases such as hypercholesterolemia and atherosclerosis, these important functions of the vascular endothelium are strongly impaired. One of the major reasons for this so-called endothelial dysfunction is the increased vascular generation of reactive oxygen species such as superoxide and peroxynitrite. We aimed to investigate whether superoxide and peroxynitrite impacts on the expression and function of sGC and if such a mechanism occurs in a hypercholestemia-induced atherosclerosis. Our experiments with isolated rat aortic rings showed that extracellular superoxide has no effect on expression and function of sGC, while subjection of these rings to continuously generated extracellular peroxynitrite reduced sGC activity. Furthermore, intracellular superoxide as generated by LY85385 almost completely inhibited sGC-activity and increased its expression. In the cholesterol-fed White New Zealand rabbit, we found a 3.5-fold upregulation of sGC, while basal and NO-stimulated sGC-activities were only slightly enhanced and the vasodilator potency of SNAP was decreased by 10-fold. A great portion of the overexpressed dysfunctional sGC is located in intimal lesions. Finally, platelet sGC-activity and the anti-aggregatory effect of SNAP were not changed. These data suggest that endothelial dysfunction in hypercholesterolemia is associated with an oxidative stress-dependent and reversible overexpression of a dysfunctional vascular sGC, while inhibition of platelet sGC-activity is most likely not involved in hypercholesterolemia-induced platelet hyperreactivity.
Francois
Michèle
M
Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Moorenstr. 5, 40225 Düsseldorf, Germany.
Kojda
Georg
G
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D001808:Blood Vessels / Q000201:enzymology; D006152:Cyclic GMP / Q000502:physiology*; D006162:Guanylate Cyclase; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase
D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP