Abdominal aortic aneurysm (AAA) is a common degenerative condition with high mortality in older men. Elective surgical or endovascular repair is performed to prevent rupture of large AAAs. In contrast, despite gradual expansion, small AAAs have a low risk of rupture, and there is currently no well-defined treatment strategy for them. Therefore, a pharmacological approach for AAA is expected in the clinical setting. Indeed, several therapeutic effects of pharmacological agents have been reported in experimental models, and some agents have undergone clinical trials. Treatment with statins, angiotensin-converting enzyme-inhibitors, antibiotics, and anti-inflammatory agents appears to inhibit the growth rate of AAA in humans. However, as the sample size and follow-up period were limited in these studies, a large randomized study with long-term follow-up of small AAA should be performed to clarify the effect of these agents. Recently, the regression of AAA using molecular pharmacological approaches was reported in experimental studies. The characteristics of these strategies are the regulation of multiple molecular mediators and the signalling networks associated with AAA formation. On the basis of the results of these investigations, it may be possible to repair the injured aortic wall and obtain the remission of AAA using pharmacological therapy.

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Key Words: RANKL Ⅲ vascular calcification Ⅲ BMP-2 Ⅲ MGP Ⅲ estrogen V ascular calcification is one of the major complications of cardiovascular disease and an independent risk factor for myocardial infarction and cardiac death, 1 among other outcomes. Arterial calcification is also associated with osteoporosis, especially in postmenopausal women. 2 Recent evidence strongly suggests the biological linkages on both disease mechanisms based on the presence of bone-related proteins 3 and bone-related cells at the site of calcification. 4 Accordingly, a triad of key proteins in bone metabolism has emerged as new players in cardiovascular diseases: RANK (the receptor activator of nuclear factor B), the RANK ligand (RANKL), and osteoprotegerin (OPG).In bone, RANKL and OPG are expressed in osteoblasts, and the receptor RANK is expressed in osteoclast cells. The major role of RANKL in bone is the stimulation of osteoclast activity 5 and inhibition of osteoclast apoptosis. 6 RANKL binds not only to RANK but also to OPG,7,8 which is secreted as a soluble protein that lacks transmembrane and cytoplasmic domains. Because of this peculiarity of a decoy receptor, the major biological action described for OPG has been through the binding to RANKL and consequent inhibition of RANK stimulation, then decreasing the osteoclast differentiation and activity in bone. 7,8 OPG-deficient mice develop severe osteoporosis resulting from marked increase in osteoclast activation, and interestingly two-thirds of the animals have profound vascular medial calcification. 9 Similar to OPG-deficient mouse phenotype, postmenopausal women also have high incidence of osteoporosis and vascular calcification, 10 which suggests that RANK-RANKL system may work not only in osteoporosis but also in arterial calcification.

Background-Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)-B, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-B and ets by using chimeric decoy oligodeoxynucleotides (ODN). Methods and Results-AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-B and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared with control, accompanied by a reduction of MMP expression. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with chimeric decoy ODN. Importantly, transfection of chimeric decoy ODN demonstrated potent inhibition of aneurysmal dilatation compared with NF-B decoy ODN alone, whereas scrambled decoy ODN had no effects. Interestingly, the migration of macrophages was significantly inhibited by chimeric decoy ODN. Conclusions-We