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

Shih-Hung Tsai,Yi-Jen Peng,Shing-Jong Lin,Po-Hsun Huang,Jen-Chun Wang,Jaw-Wen Chen,Yu-Juei Hsu,Chien-Hsing Lee

doi:10.1038/srep28612

Abstract

Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α 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-1α. 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-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens.

Highlights

Medications to reduce vascular inflammation and inhibit matrix metalloproteinase (MMPs) have been proposed to treat growing Abdominal aortic aneurysm (AAA), recent clinical trials have found that mast cell stabilizers and doxycycline failed to reduce aneurysm growth and had no impact on AAA repair management[13,14]
While our initial in vitro experiments showed that DFO attenuated AngII-induced endothelial dysfunction and activation, we unexpectedly found that DFO augmented the severity of AngII-induced AAA, partially due to an aberrant increased HIF-1α, MMP-2 and MMP-9 expression
We found that DFO attenuated AngII-induced JNK, ERK1/2 and Reactive oxygen species (ROS) production

Summary

Introduction

Medications to reduce vascular inflammation and inhibit MMPs have been proposed to treat growing AAA, recent clinical trials have found that mast cell stabilizers and doxycycline failed to reduce aneurysm growth and had no impact on AAA repair management[13,14]. Iron is involved in the pathogenesis of AAA with oxidative stress and inflammation, both in human AAA tissues and in AngII-induced AAA in ApoE−/− mice[17]. Deferoxamine (DFO) could ameliorate oxidative stress, inflammatory cytokines productions, macrophage infiltration, NF-kB activation and adhesion molecule expression in several animal models, including in treating atherosclerotic vascular diseases by reducing oxidative stress and inflammation[18,19,20,21]. We provide a rationale for using pharmacological HIF-1αinhibitors as an adjunctive medical therapy for AAA

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Results

Conclusion