Abstract
We have previously shown that eNOS uncoupling mediates abdominal aortic aneurysm (AAA) formation in hph-1 mice. In the present study we examined whether recoupling of eNOS prevents AAA formation in a well-established model of Angiotensin II-infused apolipoprotein E (apoE) null mice by targeting some common pathologies of AAA. Infusion of Ang II resulted in a 92% incidence rate of AAA in the apoE null animals. In a separate group, animals were treated orally with folic acid (FA), which is known to recouple eNOS through augmentation of dihydrofolate reductase (DHFR) function. This resulted in a reduction of AAA rate to 19.5%. Imaging with ultrasound showed that FA markedly inhibited expansion of abdominal aorta. FA also abolished elastin breakdown and macrophage infiltration in the AAA animals. The eNOS uncoupling activity, assessed by L-NAME-sensitive superoxide production, was minimal at baseline but greatly exaggerated with Ang II infusion, which was completely attenuated by FA. This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability. Furthermore, the expression and activity of DHFR was decreased in Ang II-infused apoE null mice specifically in the endothelial cells, while FA administration resulted in its recovery. Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.
Highlights
Abdominal aortic aneurysms (AAA) is a disease that affects the adult population, responsible for more than 70,000 deaths annually in those over the age of 65 [1]
Bioavailability, recoupled endothelial nitric oxide synthase (eNOS), and increased nitric oxide production. These data reveal a novel role of eNOS uncoupling in the development of AAA in angiotensin II (Ang II)-infused apolipoprotein E (apoE) null mice, which is exploited by an oral treatment of folic acid (FA) that improves eNOS function to attenuate AAA. These data further confirm a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of dihydrofolate reductase (DHFR) to restore eNOS function
Oral FA treatment significantly reduced this incidence to 19.5% (p,0.001, n = 41), indicating that FA is effective in the prevention of AAA in the Ang II-infused apoE null model
Summary
Abdominal aortic aneurysms (AAA) is a disease that affects the adult population, responsible for more than 70,000 deaths annually in those over the age of 65 [1]. Studies into the underlying mechanisms of this condition show several important processes, such as inflammation, matrix degradation, and remodeling [3,4,5,6]. As all of these processes are regulated to some degree by reactive oxygen species (ROS), oxidative stress plays an important role in the pathogenesis of AAA in both animal models [7,8,9,10] and humans [11,12]. The role that endothelial cells or dysfunctional eNOS plays in the development of AAA warrants further investigation
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