Heme oxygenase-1 deficiency exacerbates angiotensin II-induced aortic aneurysm in mice.
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.
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Yen-Chun
YC
Ho
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Meng-Ling
ML
Wu
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Pei-Yu
PY
Gung
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Chung-Huang
CH
Chen
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.|Graduate Institute of Basic Medical Science and Metabolomic Research Center, China Medical University, Taichung, Taiwan.
Cheng-Chin
CC
Kuo
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Graduate Institute of Basic Medical Science and Metabolomic Research Center, China Medical University, Taichung, Taiwan.
Shaw-Fang
SF
Yet
D000743:Anemia, Hemolytic / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism
D016207:Cytokines; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9
Pathology Section; abdominal; aortic aneurysm; heme oxygenase-1; inflammation; oxidative stress