Reduced Atherosclerotic Burden in Subjects With Genetically Determined Low Oxidative Stress

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 33; no. 2; pp. 406 - 412
• Main Authors: Violi, Francesco, Pignatelli, Pasquale, Pignata, Claudio, Plebani, Alessandro, Rossi, Paolo, Sanguigni, Valerio, Carnevale, Roberto, Soresina, Annarosa, Finocchi, Andrea, Cirillo, Emilia, Catasca, Elisa, Angelico, Francesco, Loffredo, Lorenzo
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2013
• Subjects: Adult; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Atherosclerosis - prevention & control; Biomarkers - blood; Biomarkers - urine; Brachial Artery - physiopathology; Carotid Intima-Media Thickness; Case-Control Studies; Chi-Square Distribution; Female; Genetic Predisposition to Disease; Humans; Isoprostanes - blood; Isoprostanes - urine; Italy; Linear Models; Membrane Glycoproteins - blood; Membrane Glycoproteins - genetics; Middle Aged; NADPH Oxidase 2; NADPH Oxidases - blood; NADPH Oxidases - genetics; Nitrates - blood; Nitrites - blood; Obesity - enzymology; Obesity - pathology; Obesity - physiopathology; Oxidative Stress - genetics; Phenotype; Predictive Value of Tests; Vasodilation
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.112.300438

OBJECTIVE—NADPH oxidase, one of the most important enzymes producing reactive oxidant species, is suggested to play a role in experimental atherosclerosis, but its role in human atherosclerosis is still unclear. We hypothesized that a reduced activity of NADPH oxidase might be linked to a reduced atherosclerotic burden. METHODS AND RESULTS—Thirty-one women carriers of hereditary deficiency of NOX2, the catalytic subunit of NADPH oxidase, were matched for sex and age with 31 controls and 31 obese women. Flow-mediated dilation and intima-media thickness, 2 surrogate markers of atherosclerosis, serum activity of NOX2, urinary isoprostanes, serum levels of nitrite/nitrate, and platelet production of isoprostanes and nitrite/nitrate were determined. Compared with controls (5.7±3.0% and 0.60±0.11 mm), carriers of NOX2 deficiency had higher flow-mediated dilation (9.2±5.0%; P<0.001) and lower intima-media thickness (0.50±0.11 mm; P=0.002), whereas obese women had lower flow-mediated dilation (3.2±2.1%; P=0.007) and higher intima-media thickness (0.71±0.15 mm; P<0.001). Compared with controls, carriers of NOX2 deficiency had lower urinary isoprostanes (132.6±87.3 versus 82.3±46.0 pg/mg creatinine; P=0.007) and serum NOX2 activity (24.9±19.3 versus 12.8±11.9 pg/mL; P=0.004) and higher serum nitrite/nitrate (23.8±7.6 versus 30.5±6.3 µmol/L; P<0.001), whereas obese women had higher urinary isoprostanes (132.6±87.3 versus 182.2±84.6 pg/mg creatinine; P=0.008) and serum NOX2 activity (24.9±19.3 versus 36.1±18.6 pg/mL; P=0.008) and lower serum nitrite/nitrate (23.8±7.6 versus 12.6±4.2 µmol/L; P<0.001). Flow-mediated dilation correlated with intima-media thickness (r=–0.433; P<0.001), serum NOX2 activity (r=–325; P<0.001), and urinary isoprostanes (r=–0.314; P=0.002). Ex vivo study showed that, compared with controls, platelets from carriers of NOX2 deficiency had lower isoprostanes (P<0.001) and higher nitrite/nitrate (P<0.001), whereas platelets from obese women had higher isoprostanes (P<0.001) and lower nitrite/nitrate (P=0.013). CONCLUSION—The study shows reduced atherosclerotic burden in carriers of NOX2 deficiency, suggesting that oxidative stress generated by this enzymatic pathway is implicated in human atherosclerosis.