Abstract 21225: Progressively Deteriorated Uncoupling of eNOS Induces Abdominal Aortic Aneurysm in Ang II-infused Hph-1 Mice: Prevention by Folic Acid
Introduction: We have previously shown that angiotensin II (Ang II) uncouples eNOS via NAD(P)H oxidase-dependent mechanisms, resulting in self-propagation of reactive oxygen species.
Hypothesis: Ang II and uncoupled eNOS synergistically induces vascular dysfunction.
Methods and Results: Tetrahydrobiopterin (H4B) deficiency subsequent to a mutation in GTPGH1 induces hyperphenylalaninemia in mice. We characterized these hph-1 mice and found that eNOS is uncoupled at baseline. WT and hph-1 mice were infused with Ang II infusion for 14 days. Mean blood pressure (MBP) monitored by tail-cuff and telemetry methods, increased in both groups up to day 10. While MBP in WT mice continued to rise, it started to decline in hph-1 mice, which was associated with sudden death (22.2%). Immediate post-mortem inspection revealed rupturing abdominal aortic aneurysm (AAA). Approximately 61.1% of the surviving hph-1s developed severe AAA, resulting in a total incidence rate of 83.3%. Importantly, eNOS uncoupling in the abdominal aortic segments was progressively deteriorated during Ang II infusion, as L-NAME sensitive superoxide production was markedly and time-dependently further increased. This was accompanied by progressively deteriorated deficiencies in H4B and nitric oxide bioavailability. We have previously shown that Ang II uncouples eNOS via a deficiency in H4B salvage enzyme dihydrofolate reductase (DHFR), which can be corrected by folic acid to recouple eNOS. Of note, DHFR expression was reduced in hph-1 mice at baseline, and it was substantially further diminished by Ang II. Intriguingly, folic acid completely prevented AAA development in Ang II-infused hph-1 mice, while attenuating progressive deterioration of eNOS uncoupling. Folic acid also prevented elastin breakdown and collagen remodeling, as well as adventitial hypertrophy observed in the non-aneurysmal thoracic aortic segments.
Conclusions: Progressively deteriorated uncoupling of eNOS induces AAA formation in Ang II-infused hph-1 mice. This is mediated by deteriorated deficiencies in DHFR expression, and in H4B and nitric oxide bioavailability. Folic acid extremely potently prevents AAA formation by attenuating progressive deterioration of eNOS uncoupling.
- © 2010 by American Heart Association, Inc.