Blockade of the angiotensin II type 1 receptor increases bone mineral density and left ventricular contractility in a mouse model of juvenile paget disease.
Blockade of the angiotensin II type 1 receptor increases bone mineral density and left ventricular contractility in a mouse model of juvenile paget disease.
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DOI：
10.1016/j.ejphar.2019.172519
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发表时间：
2019-09
影响因子：
5
通讯作者：
T. Tsuruda;T. Funamoto;N. Udagawa;S. Kurogi;Yuko Nakamichi;M. Koide;E. Chosa;Y. Asada;K. Kitamura
中科院分区：
文献类型：
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作者：
T. Tsuruda;T. Funamoto;N. Udagawa;S. Kurogi;Yuko Nakamichi;M. Koide;E. Chosa;Y. Asada;K. Kitamura
幼年型佩吉特病（JPD 1）是一种常染色体隐性遗传疾病，其特征是骨保护素缺乏导致骨转换异常迅速。它的骨骼外表现，如高血压和心力衰竭，提示骨骼和心血管系统成分共享的发病机制。尽管如此，抗高血压药物对骨形态计量学的影响仍然未知。我们给予缺乏骨保护素基因的8周龄雄性小鼠血管紧张素II 1型受体阻滞剂奥美沙坦（5 mg/kg/天），伴或不伴1 μg/kg/min血管紧张素II输注，持续14天。奥美沙坦治疗降低收缩压，超声心动图显示左心室收缩力增加。三维显微计算机断层扫描显示，奥美沙坦治疗增加了胫骨的骨小梁体积（假手术，+176%;血管紧张素II输注，+335%）、矿物质密度（假手术，+150%;血管紧张素II输注，+313%）和骨小梁数量（假手术，+407%;血管紧张素II输注，+622%）。奥美沙坦增加皮质矿物质密度（假手术，+19%;血管紧张素II输注，+24%），减少皮质骨截面面积（假手术，-16%;血管紧张素II输注，-18%），厚度减少（假手术，-18%;血管紧张素II输注，-31%），并减少胫骨的陷窝面积（假手术，-41%;血管紧张素II输注，-27%）。在股骨中观察到类似趋势。此外，奥美沙坦降低血管紧张素II诱导的血浆中抗酒石酸酸性磷酸酶浓度升高，但既不影响I型前胶原N-末端前肽，也不影响核因子κ B配体的受体激活剂。我们的数据表明，血管紧张素II 1型受体的阻断剂改善骨脆弱性，并有助于维持骨保护素缺乏小鼠心脏结构的完整性。
Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 μg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, −16%; angiotensin II infusion, −18%), decreased thickness (sham, −18%; angiotensin II infusion, −31%), and decreased the lacunar area (sham, −41%; angiotensin II infusion, −27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.