Thiol-dependent redox modulation of soluble guanylyl cyclase

Background Following prolonged exposure to NO, soluble guanylyl cyclase (sGC) becomes desensitized and fails to respond to additional NO stimulation. We showed that sGC is desensitized by S-nitrosylation in vitro, in primary smooth muscle cells (SMC) and in tissues and identified two cysteines (Cys) targeted by this post-translational modification that are involved in sGC desensitization [1]. We recently discovered that nitroglycerin (GTN) induces Snitrosylation of sGC. We also showed that chronic treatment with GTN or acute treatment with S-nitroso-cysteine (CSNO), which lead to impaired relaxation in vivo, were accompanied by decreased GTNor NO-stimulated cGMP production and characterized by strong S-nitrosylation of sGC. These observations suggested that desensitization of sGC by S-nitrosylation could be a mechanism of tolerance [2]. Based on observations by others that chronic GTN treatment increases ROS species and that oxidants exposure of cells impaired sGC response to NO, we hypothesize that desensitization of sGC by redox-dependent modification of its Cys is a mechanism underlying the loss of vascular reactivity in some oxidative vascular diseases.