Abstract 18077: Folic Acid Attenuates Abdominal Aorta Aneurysms in Ang II-infused apoE Null Mice
We have recently shown that severely uncoupled eNOS plays a causal role in the development of abdominal aortic aneurym (Hypertension 2012, 59(1):158-66) in an angiotensin II (Ang II) infused hph-1 mice. We have also shown that this phenotype can be completely attenuated by recoupling eNOS with oral folic acid (FA) administration, which restores eNOS cofactor tetrahydrobiopterin (H4B) bioavailability via restoration of H4B salvage enzyme dihydrofolate reductase. In the present study we investigated a potential role of eNOS uncoupling in AAA formation in Ang II-infused apoE null mice. Three to five month old apoE null mice were infused with Ang II (1000 ng/kg/min) for 4 weeks using implanted Alzet osmotic pumps. Animals were fed normal chow or customerized FA chew (15 mg/kg/day) two days prior to Ang II infusion and throughout the study period of 4 weeks. Of note, 15 out of 16 Ang II infused apoE null mice (93.7%) on normal chow developed AAA. With FA treatment, the incidence rate of AAA dropped to 3 out of 14 (21.4%). Aortic superoxide production determined by electron spin resonance showed a 2.67±0.15 fold increase with Ang II treatment in apoE null mice, which was attenuated to 1.75±0.01 fold by FA administration (n=6 each). L-NAME sensitive superoxide production, which reflects eNOS uncoupling activity, was also measured. Ang II treated apoE null mice have greatly increased eNOS dysfunction with 2.22±0.2 fold increase in L-NAME sensitive superoxide production, a marked exaggeration from the modest uncoupling of eNOS in apoE null mice at baseline of 1.17±0.06 fold. Treatment with FA restored eNOS function, resulting in -1.22±0.4 fold change in L-NAME sensitive superoxide. These data demonstrate that an oral treatment of FA is extremely effective in reducing the incidence of AAA in a second model of AAA of Ang II-infused apoE null mice, and it suggests that this protective effect of FA is at least partly attributed to the restoration of eNOS function in this particular model.
- © 2012 by American Heart Association, Inc.