Mice Lacking Hypertension Candidate Gene ATP2B1 in Vascular Smooth Muscle Cells Show Significant Blood Pressure Elevation
Mice Lacking Hypertension Candidate Gene ATP2B1 in Vascular Smooth Muscle Cells Show Significant Blood Pressure Elevation
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DOI：
10.1161/hypertensionaha.110.165068
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发表时间：
2012-04-01
期刊：
影响因子：
8.3
通讯作者：
Umemura, Satoshi
中科院分区：
文献类型：
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作者：
Kobayashi, Yusuke;Hirawa, Nobuhito;Umemura, Satoshi
我们之前曾报道，ATP2B1是日本大规模人群中高血压易感性的基因之一，最近在欧洲人和韩国人中也出现了这种情况。ATP2B1编码质膜钙ATPase亚型1，在细胞内钙动态平衡中起关键作用。此外，还提示ATP2B1在血管平滑肌收缩中起重要作用。由于ATP2B1基因敲除(KO)小鼠是胚胎致死的，我们使用Cre-loxP系统培育了血管平滑肌细胞特异性的ATP2B1基因敲除小鼠，以阐明ATP2B1与高血压的关系。与对照组相比，KO组小鼠主动脉中ATP2B1基因和蛋白的表达水平显著降低。KO小鼠用尾套法和放射性遥测法测得的收缩压显著高于对照组。与ATP2B1类似，KO小鼠血管平滑肌细胞Na+-Ca~(+)交换异构体1mRNA表达降低。而在KO小鼠中，ATP2B4表达增加。培养的KO小鼠血管平滑肌细胞不仅在基础状态下细胞内钙离子浓度升高，而且在苯肾上腺素刺激状态下也表现出细胞内钙离子浓度升高。此外，KO小鼠股动脉血管环上苯肾上腺素诱导的血管收缩作用显著增强。这些结果表明，ATP2B1通过改变血管平滑肌细胞的钙转运和血管收缩作用而发挥重要的血压调节作用。(高血压。2012年；59：854-860。)。在线数据补充
We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na+-Ca2(+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells. (Hypertension. 2012;59:854-860.). Online Data Supplement