Abstract 16881: NOX Isoforms and Development of Abdominal Aortic Aneurysm
Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently shown a causal role of uncoupled eNOS in this disease. While others and we have also shown that NADPH oxidase (NOX) lie upstream of uncoupled eNOS, the specific isoforms(s) and role that they play in AAA has not been examined. In this study, we used a recently established model of AAA, the Ang II infused hph-1 mice, to examine the specific role of the major isoforms of NOX in the development of AAA. We generated double knockouts of hph-1-NOX1 and hph-1-NOX2, and also inhibited NOX4 expression in hph-1 animals with in vivo RNAi. Ang II was infused into the animals for 2 weeks using an osmotic pump. The results show that the incidence rate of AAA substantially dropped from 76% in Ang II infused hph-1 mice to 4% and 16% in hph-1-NOX1 and hph-1-NOX2 double knockouts, respectively, while hph-1-NOX4 siRNA animals did not have significantly different incidence (83%). By week 2, the sizes of abdominal aortas of the hph-1-NOX1 and hph-1-NOX2 double knockouts, determined by ultrasound analyses, were significantly smaller at 1.3±0.08 and 1.4±0.08 mm2, respectively, when compared to hph-1 alone, at 3.1±0.27 mm2. Furthermore, aortic nitric oxide and H4B bioavailability were markedly improved in the double knockouts, while the total superoxide production and eNOS uncoupling activity were markedly reduced. These effects seemed attributed to an endothelial cell specific improvement in the expression and activity of dihydrofolate reductase (DHFR), a salvage enzyme for H4B whose deficiency has been shown to induce eNOS uncoupling and AAA formation in both hph-1 and apoE null animals. Taken together, these data indicate that NOX isoforms 1 or 2 lies upstream of DHFR deficiency and eNOS uncoupling to induce AAA formation. These data once again demonstrate the importance of uncoupled eNOS in the development of AAA, and a novel role of NOX1/2 isoforms in the process. These findings may facilitate new therapeutic options for the treatment of the disease.
Author Disclosures: K.L. Siu: None. H. Cai: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.