Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2.
Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-beta(1) subunit expression in a concentration-dependent manner. The maximal reduction in sGC-beta(1) subunit expression was achieved with 1 ppm lead. Vitamin C (30 micromol/L) partially restored sGC-beta( 1) subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-beta(1) subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 micromol/L) and with rofecoxib (1 micromol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-beta(1) subunit induced by lead in the rat vascular wall.
Courtois
Elise
E
Cardiovascular Research and Hypertension Laboratory, Fundación Jiménez Díaz, Madrid, Spain.
Marques
Maria
M
Barrientos
Alberto
A
Casado
Santos
S
López-Farré
Antonio
A
D000818:Animals; D001011:Aorta / Q000201:enzymology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D007854:Lead / Q000494:pharmacology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012995:Solubility; D013449:Sulfonamides; D013450:Sulfones; D013481:Superoxides / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007546:Isoquinolines; D007783:Lactones; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D013481:Superoxides; D007854:Lead; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D006162:Guanylate Cyclase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide