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

Background and aims: We aimed to determine the effect of HIF-1 alpha, the main regulatory subunit of the hypoxia inducible factor 1 (HIF-1), on the development of the abdominal aortic aneurysm (AAA). Methods: AAA was induced in ApoE(-/-) mice by angiotensin. (AngII) infusion. In vivo silencing of HIF-1 alpha was achieved by transfection of lentivirus expressing HIF-1 alpha shRNA. Results: Time course analysis of the Ang. infusion model revealed that HIF-1 alpha was persistently upregulated during a 28-day period of AAA development. Silencing of the HIF-1 alpha 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-1 alpha also alleviated infiltration of macrophages (38.8 +/- 14.7 vs. 11.4 +/- 4.4 macrophages/0.1 mm(2), p = 0.0006) and neovascularity (5.56 +/- 2.14 vs. 1.27 +/- 1.05 microvessels/0.1 mm(2), p = 0.0008) in the Ang. infusion model, at day 28. The activity of MMP-2 and MMP-9 was also decreased by knockdown of HIF-1 alpha. The early increased expression of pro-inflammatory factors, angiogenic factors, and MMPs during AAA induction was alleviated by HIF-1 alpha silencing. Conclusions: Activation of HIF-1 signaling pathway participates in the Ang II-induced AAA formation in mice. (C) 2016 Elsevier Ireland Ltd. All rights reserved.