NOX isoforms in the development of abdominal aortic aneurysm

Abstract

Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…It has been reported that deletion of p47 phox , which activates Nox1 and Nox2, prevents ANG II-induced AAA formation in apoEϪ/Ϫ mice (1048). Deletion of Nox1, Nox2, or Nox4 further diminished ANG II-dependent AAA and eNOS uncoupling in these mice (975). Systemic AMPK␣2 deficiency, but not bone marrow deficiency, in apoEϪ/Ϫ mice prevents ANG II-induced AAA development.…”

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

“…Mechanistically, administration of a NOX4 inhibitor or siRNA abolished the homocysteine‐induced adventitial activation (Liu et al ., ). Moreover, NOX4 deficiency inhibited AAA formation‐induced by Ang II in mice with hyperphenylalaninaemia and uncoupled eNOS (Siu et al ., ). Thus, NOX4 mediates the adverse effects of homocysteine in adventitial inflammation and AAA formation (Liu et al ., ).…”

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

“…Myriad enzymes contribute to ROS generation, of which NOX family is dedicated generators of intracellular superoxide and hydrogen that strongly involve in redox signaling under healthy and pathological conditions [20][21][22]. NOX family consists of five isoforms including NOX1, NOX2, NOX3, NOX4 and NOX5, which accelerate ROS production in the vasculature [23][24][25][26][27].…”