Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases

Hypoxia inducible factor-1 alpha (HIF-1 alpha) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1 alpha expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1 alpha. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1 alpha and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1 alpha and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1 alpha can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1 alpha inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1 alpha is pivotal for the development of AAA. Our study provides a rationale for using HIF-1 alpha inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens.