AT2 receptor stimulation inhibits phosphate-induced vascular calcification
AT2 receptor stimulation inhibits phosphate-induced vascular calcification
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DOI：
10.1016/j.kint.2018.07.028
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发表时间：
2019-01-01
影响因子：
19.6
通讯作者：
Horiuchi, Masatsugu
中科院分区：
文献类型：
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作者：
Kukida, Masayoshi;Mogi, Masaki;Horiuchi, Masatsugu
血管钙化是动脉粥样硬化和慢性肾病患者的常见现象。肾素-血管紧张素系统在心血管重塑的发病机制中发挥作用。在这里，我们检验了血管紧张素 II 2 型受体 (AT2) 刺激对磷酸盐诱导的血管钙化具有抑制作用的假设。在体内，与野生型和 AT2 敲除小鼠 (AT2KO) 相比，平滑肌细胞特异性 AT2 过表达小鼠 (smAT2-Tg) 中由腺嘌呤和高磷酸盐饮食诱导的胸主动脉钙化明显减弱。同样，smAT2-Tg 小鼠中相关成骨和血管平滑肌细胞标记基因的 mRNA 水平没有变化，而野生型小鼠中它们的表达因高磷酸盐饮食而显着改变。离体胸主动脉切片在补充有无机磷酸盐的培养基中培养。与野生型小鼠相比，smAT2-Tg 小鼠的主动脉环显示出较少的血管钙化。在体外，与其他两组小鼠相比，smAT2-Tg 小鼠的原代血管平滑肌细胞中高磷酸盐介质诱导的钙沉积明显减弱。为了评估潜在的机制，我们研究了 PPAR-gamma 的作用，我们之前报道过 PPAR-gamma 是 AT2 刺激的可能下游效应器之一。 PPAR-γ拮抗剂治疗减弱了在喂食腺嘌呤和高磷酸盐饮食的 smAT2-Tg 小鼠中观察到的对血管钙化的抑制作用。我们的结果表明 AT2 激活代表了对抗血管钙化的内源性保护途径。它的刺激可以有效减少慢性肾病患者的不良心血管事件。
Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-gamma, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-gamma antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.