Abstract 468: HIF-1α Mediates Initiation and Progression of Experimental Abdominal Aortic Aneurysms
Abdominal aortic aneurysm (AAA) is a life-threatening chronic disease. Although low mural oxygen tension is present in the aneurysmal aorta, with increased hypoxia inducible factor (HIF)-1α expression, the role of HIF-1α in AAA pathogenesis remains uncertain. These experiments separately examined the influences of myeloid cell-specific HIF-1α deletion, as well as pharmacologic HIF-1α inhibition, on experimental AAA progression. Methods: AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion in myeloid cell-specific HIF-1α conditional knockout (Lyz2 Cre+/HIF-1α Flox+/+) or control (HIF-1α Flox+/+) mice, as well as C57BL/6J mice treated with HIF-1α inhibitors or vehicle. AAA formation and progression was evaluated in vivo via ultrasonography, and histology at sacrifice. Results: HIF-1α mRNA expression was remarkably elevated in aneurysmal (PPE) as compared to non-aneurysmal (PBS), aortae. Flow cytometry detected nearly 65% of aortic CD11b+ myeloid cells expressed HIF-1α. Myeloid cell HIF-1α deletion reduced time-dependent aneurysmal enlargement noted following PPE infusion. Similar inhibition was observed in WT mice following daily treatment with acriflavine or doxorubicin (1 mg/kg), beginning 3 days prior to PPE infusion. Histologically, both myeloid cell HIF-1α deletion and pharmacologic HIF-1α inhibition attenuated medial elastin degradation and smooth muscle cell depletion, with reduced aortic mural macrophage and neovessel density compared to the corresponding controls. Conclusion: HIF-1α is an essential modulator of AAA pathogenesis, thus representing a novel pharmacologic target for medical disease management.
Author Disclosures: B. Xu: None. N. Fujimura: None. H. Deng: None. H. Xuan: None. Y. Furusho: None. K.J. Glover: None. M. Gerritsen: None. G.C. Gurtner: None. S.A. Michie: None. R.L. Dalman: None.
- © 2015 by American Heart Association, Inc.