Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway
Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway
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DOI：
10.1111/j.1365-2362.2008.01930.x
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发表时间：
2008-04-01
影响因子：
5.5
通讯作者：
Badimon, J. J.
中科院分区：
文献类型：
--
作者：
Choi, B. G.;Vilahur, G.;Badimon, J. J.
背景观察研究表明更年期与血管钙化之间存在密切关系。核因子 kappa Beta 配体受体激活剂 (RANKL) 和骨保护素 (OPG) 是骨重塑和调节血管钙化的关键调节剂。我们评估了卵巢切除术通过 OPG/RANKL 轴增加血管钙化的假设。材料和方法年龄匹配的性成熟兔子被随机分为卵巢切除术（OVX，n = 12）或假手术（SHAM，n = 12）。术后 1 个月，15 个月的 0.2% 胆固醇饮食和内皮球囊剥脱（第 1 个月和第 3 个月）诱导动脉粥样硬化。在第9个月和第15个月时，通过磁共振成像（MRI）对主动脉粥样硬化进行体内评估。处死时，收获主动脉进行离体微计算机断层扫描（mu CT）和血管组织的分子分析。结果 OVX中的血管钙化密度和钙化颗粒数量显着高于SHAM（8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3)，P = 0.042 和 94 +/- 26 对比 33 +/- 7 颗粒 cm(-3)，P = 0.046。通过最大钙化颗粒所对的弧角来评估钙化形态，显示各组之间没有差异（OVX 33 +/- 7 度与 SHAM 33 +/- 5 度，P = 0.99）。通过蛋白质印迹分析，OVX 使血管 OPG:RANKL 比率增加了 66%，P = 0.029，主要是通过降低 RANKL (P = 0.019)。第 9 个月时，MRI 显示 OVX 和 SHAM 之间的动脉粥样硬化体积没有差异，并且到研究结束时也没有看到显着变化。 结论 与骨相比，血管 OPG:RANKL 比率因卵巢切除术而增加，相应的动脉钙化增加了四倍。这种直接器官特异性反应可以解释绝经后妇女骨质疏松症与钙化动脉粥样硬化的共病关联。
Background Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappa Beta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis.Materials and methods Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (mu CT) and molecular analysis of the vascular tissue.Results Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees, P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study.Conclusions In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.