Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

• Published in: American journal of physiology. Heart and circulatory physiology 2012-09, Vol.303 (5), p.H597-H604
• Main Authors: Crassous, Pierre-Antoine, Couloubaly, Samba, Huang, Can, Zhou, Zongmin, Baskaran, Padmamalini, Kim, David D, Papapetropoulos, Andreas, Fioramonti, Xavier, Durán, Walter N, Beuve, Annie
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Arterioles - enzymology; Arterioles - physiopathology; Blood Pressure; Cardiology and cardiovascular system; Cardiovascular disease; Cell Line; Cells; Coronary vessels; Cyclic GMP - metabolism; Cysteine; Disease Models, Animal; Enzyme Activation; Enzymes; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Homeostasis; Human health and pathology; Hypertension - chemically induced; Hypertension - enzymology; Hypertension - physiopathology; Integrative Cardiovascular Physiology and Pathophysiology; Life Sciences; Male; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - physiopathology; Mutation; Myocytes, Smooth Muscle - enzymology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitrosation; Oxidative stress; Oxidative Stress - drug effects; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents; Signal Transduction; Soluble Guanylyl Cyclase; Time Factors; Tissues and Organs; Transfection; Vascular Resistance; Vasodilation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00138.2012

Nitric oxide (NO) by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells.