Key result
Oxidative or nitrosative stress blunts NO-stimulated cGMP production through differential cysteine modification of sGC.
Why the study?
Desensitization of soluble guanylyl cyclase by redox-dependent modification of cysteines may underlie loss of vascular reactivity in oxidative vascular diseases.
Desensitization of soluble guanylyl cyclase by S-nitrosylation may be a key mechanism underlying nitroglycerin tolerance and loss of vascular reactivity in oxidative vascular diseases.
May explain nitroglycerin tolerance in oxidative vascular disease; animal data leave open sGC cysteine modification as a therapeutic target.
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.
No takes yet. Share an insight, caveat, or question.
Baskaran et al. (2009) studied Nitric oxide resistance and oxidative vascular diseases. Oxidative and nitrosative stress was evaluated on Soluble guanylyl cyclase (sGC) activity and cysteine modification. Exposure of soluble guanylyl cyclase to oxidative or nitrosative stress leads to differential modification of cysteine residues, reducing maximal velocity of NO-stimulated cGMP production.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: