Τίτλος:
Soluble guanylyl cyclase activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Many vascular diseases are characterized by increased levels of ROS that destroy the biological activity of nitric oxide and limit cGMP formation. In the present study, we investigated the cGMP-forming ability of HMR-1766 in cells exposed to oxidative stress. Pretreatment of smooth muscle cells with H 2O2 reduced cGMP production stimulated by sodium nitroprusside (SNP) or BAY 41-2272. However, pretreatment with H 2O2 significantly increased HMR-1766 responses. Similar results were obtained with SIN-1, menadione, and rotenone. In addition, HMR-1766 was more effective in stimulating heme-free sGC compared with the wild-type enzyme. Interestingly, in cells expressing heme-free sGC, H2O 2 inhibited instead of potentiated HMR-1766 responses, suggesting that the ROS-induced enhancement of cGMP formation was heme dependent. Moreover, using truncated forms of sGC, we observed that the NH2-terminus of the β1-subunit is required for the action of HMR-1766. Finally, to study tolerance development to HMR-1766, cells were pretreated with this sGC activator and reexposed to HMR-1766 or SNP. Results from these experiments demonstrated lack of tolerance development to HMR-1766 as well as lack of cross-tolerance with SNP. We conclude that HMR-1766 is an improved sGC activator as it has the ability to activate oxidized/heme-free sGC and is resistant to the development of tolerance; these observations make HMR-1766 a promising agent for treating diseases associated with increased vascular tone combined with enhanced ROS production. Copyright © 2008 the American Physiological Society.
Συγγραφείς:
Zhou, Z.
Pyriochou, A.
Kotanidou, A.
Dalkas, G.
Van Eickels, M.
Spyroulias, G.
Roussos, C.
Papapetropoulos, A.
Περιοδικό:
American Journal of Physiology - Heart and Circulatory Physiology
Λέξεις-κλειδιά:
4 amino 5 cyclopropyl 2 [1 (2 fluorobenzyl) 1h pyrazolo[3,4 b]pyridin 3 yl]pyrimidine; ataciguat; cyclic GMP; guanylate cyclase; guanylate cyclase activator; heme; hmr 1766; hydrogen peroxide; linsidomine; menadione; nitric oxide; nitroprusside sodium; reactive oxygen metabolite; rotenone; unclassified drug, animal cell; article; beta chain; biological activity; blood vessel tone; cell culture; controlled study; cross tolerance; enzyme activation; enzyme inhibition; enzyme synthesis; immunoassay; male; nonhuman; oxidative stress; priority journal; protein expression; rat; smooth muscle fiber; vascular disease; Western blotting; wild type, Animals; Anthranilic Acids; Cercopithecus aethiops; COS Cells; Cyclic GMP; Dose-Response Relationship, Drug; Drug Tolerance; Enzyme Activation; Enzyme Activators; Guanylate Cyclase; Heme; Male; Models, Molecular; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Donors; Oxidants; Oxidative Stress; Protein Conformation; Protein Structure, Tertiary; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Sulfonamides; Transfection; Vasodilator Agents
DOI:
10.1152/ajpheart.51.2008
