Association of osteoprotegerin with human abdominal aortic aneurysm progression
Association of osteoprotegerin with human abdominal aortic aneurysm progression
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DOI：
10.1161/circulationaha.104.464727
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发表时间：
2005-06-14
期刊：
影响因子：
37.8
通讯作者：
Golledge, J
中科院分区：
文献类型：
--
作者：
Moran, CS;McCann, M;Golledge, J
背景-腹主动脉瘤（AAA）的特征是动脉中膜破坏，伴有血管平滑肌细胞丢失、单核细胞浸润和高浓度的金属蛋白酶（MMPs）和细胞因子。骨保护素（OPG）最近已被确定在动脉粥样硬化。研究了OPG在人AAA中的存在和功能重要性。方法和结果-在146例小AAA患者中，超声随访3年，血清OPG与动脉瘤生长率弱相关。Western分析显示，与动脉粥样硬化狭窄的主动脉活检相比，人AAA活检组织中OPG浓度高3倍、8倍和12倍（1.4 +/- 0.1 vs 0.5 +/- 0.1 ng/mg组织; P = 0.002），死后未患病的腹主动脉（1.4 +/- 0.1 vs 0.2 +/- 0.1 ng/mg组织; P < 0.001）和未患病胸主动脉（1.4 +/- 0.1 vs 0.1 +/- 0.06 ng/mg组织; P < 0.001）。与重组人（rh）OPG（0 - 20 ng rhOPG/10（5）个细胞/mL/24小时）孵育的健康人主动脉血管平滑肌细胞出现了细胞增殖受损（P < 0.001）、细胞凋亡增加（P <0.01）和MMP-9（92 kDa）表达增加（P < 0.001）的血管瘤表型。单核细胞THP-1细胞与1 ng rhOPG/10（5）cells/mL/24 h孵育诱导MMP-9表达增加2倍（P < 0.001），MMP-2活性增加1.5倍（P = 0.005），IL-6产生增加2倍（P = 0.02）。最后，通过血管紧张素II阻断剂厄贝沙坦处理，人AAA外植体的OPG分泌被废除，每48小时内分泌水平平均降低63.0 +/- 0.9 ng/mg组织。结论：这些发现支持OPG在人AAA生长中的作用，并提示血管紧张素II阻滞剂在减缓动脉瘤扩张中的潜在益处。
Background - Abdominal aortic aneurysm ( AAA) is characterized by destruction of the arterial media associated with loss of vascular smooth muscle cells, infiltration of mononuclear cells, and high concentration of metalloproteinases ( MMPs) and cytokines. Osteoprotegerin (OPG) has recently been identified in atherosclerosis. The presence and functional importance of OPG in human AAA was investigated. Methods and Results - In 146 men with small AAA followed up by ultrasound for 3 years, serum OPG was weakly correlated with aneurysm growth rate. Western analysis showed 3-, 8-, and 12-fold-greater OPG concentrations in human AAA biopsies compared with biopsies of atherosclerotic narrowed aorta (1.4 +/- 0.1 versus 0.5 +/- 0.1 ng/mg tissue; P = 0.002), postmortem nondiseased abdominal aorta (1.4 +/- 0.1 versus 0.2 +/- 0.1 ng/mg tissue; P < 0.001), and nondiseased thoracic aorta (1.4 +/- 0.1 versus 0.1 +/- 0.06 ng/mg tissue; P < 0.001). Healthy human aortic vascular smooth muscle cells incubated with recombinant human (rh) OPG (0 to 20 ng rhOPG/10(5) cells per 1 mL per 24 hours) developed an aneurysmal phenotype defined by impaired cell proliferation (P < 0.001), increased apoptosis ( P < 0.01), and increased MMP-9 (92 kDa) expression (P < 0.001). Incubation of monocytic THP-1 cells with 1 ng rhOPG/10(5) cells per 1 mL per 24 hours induced a 2-fold increase in MMP-9 expression (P < 0.001), a 1.5-fold increase in MMP-2 activity (P = 0.005), and a 2-fold stimulation of IL-6 production in these cells (P = 0.02). Finally, secretion of OPG from human AAA explant was abrogated by treatment with the angiotensin II blocker irbesartan, with the reduction in secreted levels averaging 63.0 +/- 0.9 ng/mg tissue per 48-hour period. Conclusions - These findings support a role for OPG in the growth of human AAA and suggest a potential benefit for angiotensin II blockade in slowing aneurysm expansion.