Abstract 18058: Circulating Tetrahydrobiopterin as a Biomarker for Abdominal Aortic Aneurysm Development, and a Predictor of Treatment Efficacies, in Angiotensin II-infused hph-1 and apoE Null Mice
Surgical treatment of the abdominal aortic aneurysm (AAA) has been met with success for aneurysms larger than 5cm. However, detection of smaller aneurysms, particularly those asymptomatic, has remained problematic, resulting in potential silent growth, sudden rupture and death. We have shown that restoration of tetrahydrobiopterin (H4B) levels via oral folic acid (FA) treatment in a novel murine model of AAA, the hph-1 mice, was successful in the prevention of AAA (Hypertension 2012, 59(1):158-66). Of note, in that study aortic levels of H4B decreased with the treatment of Ang II, which was restored by oral treatment of FA. We therefore investigated whether H4B levels can be used as a biomarker for AAA. In this study, we used both hph-1 mice as well as another established AAA model of Ang II infused apoE null mice. In apoE null mice, H4B measured using HPLC showed that in the aortas, H4B levels decreased with Ang II infusion (4.86±0.32 to 2.72±0.26 pmol/mg, n=6 each), and increased with oral administration of FA (6.60±0.62pmol/mg, n=6). A similar trend was observed when H4B was measured from plasma (3.31±0.13, 1.87±0.11, 5.80±0.30 pmol/mg, vehicle, Ang II, FA, respectively, n=6 each). Identically in hph-1 mice, aortic levels of H4B came out to be at 1.87±0.25, 0.99±0.11, 3.00±0.64, and plasma levels being 1.37±0.05, 0.92±0.06, and 2.36±0.25 pmol/mg (for vehicle, Ang II & AngII/FA respectively, n=3 each). Further, linear correlation between plasma and aortic H4B levels shows a R2 of 0.86 for the apoE null mice, and 0.85 for the hph-1, suggesting a linear relationship between the two measurements. This linear relationship between the two measurements is extremely important, as this will allow for a less invasive method of measuring local vascular H4B bioavailability, which is believed to be essential for predicting AAA development. In conclusion, these data indicate that a decreased H4B bioavailability is associated with AAA formation while a restored H4B bioavailability is associated with prevention of AAA development. Furthermore, changes in aortic H4B values are reflected in the plasma. Taken together, these data suggest that circulating H4B levels can serve as a biomarker for AAA development, as well as a predictor of treatment efficacies.
- © 2012 by American Heart Association, Inc.