Silencing of hypoxia inducible factor-1α gene attenuated angiotensin Ⅱ-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice

Abstract

Background and aimsWe aimed to determine the effect of HIF-1α, the main regulatory subunit of the hypoxia inducible factor 1 (HIF-1), on the development of the abdominal aortic aneurysm (AAA). MethodsAAA was induced in ApoE−/− mice by angiotensinⅡ (AngⅡ) infusion. In vivo silencing of HIF-1α was achieved by transfection of lentivirus expressing HIF-1α shRNA. ResultsTime course analysis of the AngⅡ infusion model revealed that HIF-1α was persistently upregulated during a 28-day period of AAA development. Silencing of the HIF-1α gene reduced the aneurysm size (2.84 ± 1.96 mm vs. 1.41 ± 0.85 mm respectively at day 28, p = 0.0002). Silencing of HIF-1α also alleviated infiltration of macrophages (38.8 ± 14.7 vs. 11.4 ± 4.4 macrophages/0.1 mm2, p = 0.0006) and neovascularity (5.56 ± 2.14 vs. 1.27 ± 1.05 microvessels/0.1 mm2, p = 0.0008) in the AngⅡ infusion model, at day 28. The activity of MMP-2 and MMP-9 was also decreased by knockdown of HIF-1α. The early increased expression of pro-inflammatory factors, angiogenic factors, and MMPs during AAA induction was alleviated by HIF-1α silencing. ConclusionsActivation of HIF-1 signaling pathway participates in the Ang Ⅱ-induced AAA formation in mice.