Wei Wang1, Baohui Xu1, Haojun Xuan1, Hiroki Tanaka1, Martin Rouer1, Keith J. Glover1, Naoki Fujimura1, Xiaolei Hu1, Mary Gerritsen1, Sara A. Michie2, Ronald L. Dalman1
1Vascular Surgery, Stanford University School of Medicine, Stanford, CA; 2Pathology, Stanford University School of Medicine, Stanford, CA.
OBJECTIVES: HIF-1α critically regulates angiogenesis, a histopathological feature of AAA disease. This study evaluated whether 2-methyoxyestradiol (2-ME) or digoxin, known HIF-1α inhibitors, modulate experimental AAAs.
METHODS: AAAs were created in male C57BL/6J mice via transient intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were treated with vehicle, 2-ME (50mg/kg/day) or digoxin (2mg/kg/day) starting prior to, or following, PPE infusion. Therapeutic efficacy was evaluated using serial aortic diameter ultrasound imaging and histological analyses at sacrifice.
RESULTS: mRNAs for HIF-1α and four genes regulated by HIF-1α were up-regulated in aneurysmal aortae. In vehicle-treated mice, aortic diameters enlarged remarkably and persistently beginning the third day following PPE infusion. Pretreatment with either 2-ME, or digoxin, significantly attenuated subsequent PPE-induced aortic expansion (Figure 1). Initiated 4 days following PPE infusion, treatment with both drugs also prevented further enlargement of existing AAAs. Histologically, treatment with 2-ME or digoxin was associated with preserved medial smooth muscle cellularity and elastic fibers and reduced mural leukocyte infiltration and angiogenesis.
CONCLUSIONS: Pharmacological inhibition of HIF-1α suppresses formation and progression of PPE-induced AAAs, suggesting the translational potential for HIF-1α inhibition in human AAA therapy.
AUTHOR DISCLOSURES: R. L. Dalman: Nothing to disclose; N. Fujimura: Nothing to disclose; M. Gerritsen: Nothing to disclose; K. J. Glover: Nothing to disclose; X. Hu: Nothing to disclose; S. A. Michie: Nothing to disclose; M. Rouer: Nothing to disclose; H. Tanaka: Nothing to disclose; W. Wang: Nothing to disclose; B. Xu: Nothing to disclose; H. Xuan: Nothing to disclose.
Posted April 2013