Abdominal aortic aneurysm (AAA) is among the top 20 leading causes of death in the United States. There is a great need for non-invasive therapeutic strategies for AAA since invasive surgical repair, by open or endovascular surgery, is still the gold standard for AAA therapy. Calcification in the artery was once thought to be a passive and degenerative process but is now considered to be regulated by catabolic (bone resorption by osteoclast) and anabolic (bone forming by osteoblast) processes similar to those that occur in bone. Most research efforts have been spent on deciphering the mechanisms of arterial calcification in stenotic disease, such as coronary and peripheral artery stenosis through the bone forming anabolic process. Our laboratory has instead been focusing on the role of bone resorbing process, since AAA is known to be associated more with catabolic processes than with anabolic processes of the artery. We have reported the osteoclastogenic activation of macrophages (OCG) in humans and in the calcium chloride (CaCl2)-induced mouse AAA (CaCl2 AAA). We subsequently identified OCG through distinct pathways in the mouse angiotensin II (AngII)-induced aneurysm (AngII AAA) as well. We have also tested the effects of bisphosphonates, which are widely used as a potent inhibitor of osteoclasts to treat osteoporosis, and showed their inhibitory effect on CaCl2 AAA. While cigarette smoking is known to be associated with arterial calcification in the medial layers, it has also been demonstrated to be one of the strongest positive risk factors for AAA. We have preliminarily found that cigarette smoke extract can induce OCG and aneurysm progression both in vitro and in vivo. The central hypothesis of this research proposal is that osteoclastogenic activation of macrophages contributes to aneurysmal degeneration, and thus inhibition of OCG leads to suppression of AAA. To test this hypothesis, we propose three distinct specific aims directed at understanding (1) the role of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced OCG in AngII aneurysm; (2) the impact of bisphosphonates with different affinities to calcification in OCG and AAA; and (3) the effect of smoking on OCG and AAA. A unique feature of this proposal is the novel pursuit of OCG as a therapeutic target of AAA. In fact, we are the first group to demonstrate the involvement of OCG in AAA. If our proposed study succeeds in defining the role of OCG in aneurysm formation, it will not only provide significant scientific knowledge about the impact of targeting osteoclastogenesis in AAA but also benefit patients with AAA by providing a novel pharmacological therapy. For example, recently it has been shown that a pharmacological treatment inhibiting OCG with a newer generation of bisphosphonates is effective for 12 months with a single injection.
Abdominal aortic aneurysm (AAA) is a leading cause of death in the United States. Because invasive treatment consisting of open surgical repair or endovascular stent graft placement is still the gold standard for AAA therapy, there is a vital need to develop a non-invasive pharmaceutical treatment for those afflicted with this debilitating illness. The proposed research should yield key information about the impact of targeting osteoclastogenesis in AAA as a novel pharmacological therapy and provide a significant benefit to those diagnosed with AAA.
