Nox4 and circulating free MPO synergistically promote aortic aneurysm formation

Myeloperoxidase (MPO)-induced oxidative stress plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). MPO protein released from activated inflammatory cells can circulate and be taken up into blood vessels, but the mechanisms that regulate vascular MPO uptake, and how this might impact abdominal aortic aneurysms (AAA) formation, are poorly understood. Given that MPO utilizes hydrogen peroxide (H2O2) to generate the oxidant hypochlorous acid (HOCl), and that Nox4 is a major producer of vascular H2O2, we hypothesized that vascular Nox4 promotes MPO uptake to cooperate in AAA formation. We found that aortic MPO uptake along with Nox4 expression and H2O2 levels were significantly increased in angiotensin II (AngII)-induced AAA mice. Increased aortic MPO uptake was also confirmed by ex vivo incubation of AngII- or calcium chloride (CaCl2)-treated aorta. Notably, global deletion of Nox4 prevented AngII-induced aortic MPO uptake ex vivo, while Nox4 KO mice were protected against AngII-induced AAA formation. Furthermore, overexpression of human MPO by liver-specific AAV in MPO KO mice increased circulating MPO levels and aortic MPO accumulation while promoting AAA formation. Vascular Nox4 expression contributes to aortic MPO uptake, providing a novel mechanistic linkage whereby MPO and Nox4 cooperate to promote AAA.