Abstract
Abdominal aortic aneurysm (AAA) is among the top 20 causes of death in the United States. Surgical repair is the gold standard for AAA treatment, therefore, there is a need for non-invasive therapeutic interventions. Aneurysms are more closely associated with the osteoclast-like catabolic degradation of the artery, rather than the osteoblast-like anabolic processes of arterial calcification. We have reported the presence of osteoclast-like cells (OLCs) in human and mouse aneurysmal tissues. The aim of this study was to examine OLCs from aneurysmal tissues as a source of degenerative proteases. Aneurysmal and control tissues from humans, and from the mouse CaPO4 and angiotensin II (AngII) disease models, were analyzed via flow cytometry and immunofluorescence for the expression of osteoclast markers. We found higher expression of the osteoclast markers tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-9 (MMP-9), and cathepsin K, and the signaling molecule, hypoxia-inducible factor-1α (HIF-1α), in aneurysmal tissue compared to controls. Aneurysmal tissues also contained more OLCs than controls. Additionally, more OLCs from aneurysms express HIF-1α, and produce more MMP-9 and cathepsin K, than myeloid cells from the same tissue. These data indicate that OLCs are a significant source of proteases known to be involved in aortic degradation, in which the HIF-1α signaling pathway may play an important role. Our findings suggest that OLCs may be an attractive target for non-surgical suppression of aneurysm formation due to their expression of degradative proteases.
Highlights
There are an estimated 1.1 million abdominal aortic aneurysms (AAAs) in the United States according to a comprehensive analysis of risk factors for Abdominal aortic aneurysm (AAA) in more than three million individuals evaluated by ultrasound imaging [1]
We previously demonstrated the ability of both RANKL and tumor necrosis factor α (TNFα) plus CaPO4 to stimulate osteoclastogenic differentiation of macrophages in vitro, indicating an additional pathway (TNFα + CaPO4) through which macrophages can be stimulated to differentiate into osteoclasts [18]
We found that osteoclastogenesis plays an important role in the development of aneurysms through stimulation of tartrate-resistant acid phosphatase (TRAP)-positive macrophages (TPMs) in the CaPO4 and angiotensin II (AngII)-infused apolipoprotein E-deficient mouse models [18,22]
Summary
There are an estimated 1.1 million abdominal aortic aneurysms (AAAs) in the United States according to a comprehensive analysis of risk factors for AAA in more than three million individuals evaluated by ultrasound imaging [1]. The risk factors for the development of AAA include age, male gender, family history, cardiovascular disease, and smoking [1,3,4]. Unless detected via imaging scans, often for other reasons, AAAs frequently remain undiagnosed until rupture. Existing guidelines suggest the option of elective surgical repair for aneurysms >5–5.5 cm in diameter [6]. The significant invasiveness and morbidity and mortality associated with surgery stresses the need for alternative non-surgical therapeutic strategies [9,10]
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