Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model.
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.
Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
Pierre-Antoine
PA
Crassous
Samba
S
Couloubaly
Can
C
Huang
Zongmin
Z
Zhou
Padmamalini
P
Baskaran
David D
DD
Kim
Andreas
A
Papapetropoulos
Xavier
X
Fioramonti
Walter N
WN
Durán
Annie
A
Beuve
D000804:Angiotensin II; D000818:Animals; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology; D001794:Blood Pressure; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D003545:Cysteine; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D015538:Nitrosation; D018384:Oxidative Stress / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014162:Transfection; D014655:Vascular Resistance; D014664:Vasodilation
D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; D000804:Angiotensin II; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D003545:Cysteine