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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1763    most recent 51.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhou, Z. Articles by Papapetropoulos, A. PubMed PubMed Citation Articles by Zhou, Z. Articles by Papapetropoulos, A.

Soluble guanylyl cyclase activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress

¹George P. Livanos and Marianthi Simou Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens, Athens; ²Laboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece; and ³Sanofi-Aventis Deutschland Gesellschaft mit beschränkter Haftung, Frankfurt am Main, Germany

Submitted 15 January 2008 ; accepted in final form 20 August 2008

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 H₂O₂ reduced cGMP production stimulated by sodium nitroprusside (SNP) or BAY 41-2272. However, pretreatment with H₂O₂ 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, H₂O₂ 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.

reactive oxygen species; cGMP; nitric oxide; soluble guanylyl cyclase