Heme oxygenase-1 deficiency exacerbates angiotensin II-induced aortic aneurysm in mice.

Yen-Chun Ho,Meng-Ling Wu,Cheng-Chin Kuo,Pei-Yu Gung,Chung-Huang Chen,Shaw-Fang Yet

doi:10.18632/oncotarget.11917

Abstract

Abdominal aortic aneurysm (AAA) is a chronic but often fatal disease in elderly population. Heme oxygenase-1 (HO-1) is a stress response protein with antioxidative and anti-inflammatory properties. HO-1 has been shown to protect against atherogenesis and arterial intimal thickening. Emerging evidences suggest that AAA and arterial occlusive disease have distinct pathogenic mechanisms. Thus, in this study we investigated the role of HO-1 in angiotensin II-induced AAA formation in HO-1+/+apoE−/− and HO-1−/−apoE−/− mice. We found that complete loss of HO-1 increased AAA incidence and rupture rate, and drastically increased aneurysmal area and severity, accompanied with severe elastin degradation and medial degeneration. Interestingly, we often observed not only AAA but also thoracic aortic aneurysm in HO-1−/−apoE−/− mice. Furthermore, reactive oxygen species levels, vascular smooth muscle cell (VSMC) loss, macrophage infiltration, matrix metalloproteinase (MMP) activity were markedly enhanced in the aneurysmal aortic wall in HO-1−/−apoE−/− mice. In addition, HO-1−/−apoE−/− VSMCs were more susceptible to oxidant-induced cell death and macrophages from HO-1−/−apoE−/− mice had aggravated responses to angiotensin II with substantial increases in inflammatory cytokine productions and MMP9 activity. Taken together, our results demonstrate the essential roles of HO-1 in suppressing the pathogenesis of AAA. Targeting HO-1 might be a promising therapeutic strategy for AAA.

Highlights

Abdominal aortic aneurysm (AAA) is a chronic but often fatal vascular disease that primarily affects older male patients and estimated to be the tenth commonest cause of mortality, responsible for ~2% of all deaths [1]
To investigate whether Heme oxygenase-1 (HO-1) has a role in AAA formation, we examined its temporal expression patterns in the abdominal aorta during the course of AAA development
We unequivocally demonstrate a crucial role of HO-1 in the pathogenesis of aortic aneurysm

Summary

Introduction

Abdominal aortic aneurysm (AAA) is a chronic but often fatal vascular disease that primarily affects older male patients and estimated to be the tenth commonest cause of mortality, responsible for ~2% of all deaths [1]. AAA is a localized dilatation of the abdominal aorta exceeding the normal diameter by more than 50% [3], characterized by chronic aortic wall inflammation, loss of medial vascular smooth muscle cells (VSMCs), and connective tissue degradation and remodeling. Reactive oxygen species (ROS) levels are markedly increased within human AAA segments compared with adjacent non-aneurysmal aortas [7] and in the aortic walls of experimental animals [5], implicating a critical role of ROS in AAA formation. Reducing ROS generation and inflammation might be useful therapeutic strategies [8, 9]

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Conclusion