Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School ofMedicine, Yokohama, Japan.
Hypertension. 2012 Apr;59(4):854-60. doi: 10.1161/HYPERTENSIONAHA.110.165068. Epub 2012 Feb 6.
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(+)-Ca(2+) 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.
我们之前报道过 ATP2B1 是日本大规模人群高血压易感性的基因之一，这一发现最近在欧洲人和韩国人中得到了验证。ATP2B1 编码质膜钙 ATP 酶同工型 1，该蛋白在细胞内钙稳态中起着关键作用。此外，有研究表明 ATP2B1 在血管平滑肌收缩中起主要作用。由于 ATP2B1 敲除（KO）小鼠是胚胎致死的，我们使用 Cre-loxP 系统生成了血管平滑肌细胞特异性 KO 的 ATP2B1 小鼠，以阐明 ATP2B1 与高血压之间的关系。与对照组小鼠相比，KO 小鼠主动脉中的 ATP2B1 mRNA 和蛋白表达水平明显降低。KO 小鼠通过尾套法和遥测法测量的收缩压明显升高。与 ATP2B1 相似，KO 小鼠血管平滑肌细胞中 Na(+)-Ca(2+)交换体同工型 1 mRNA 的表达减少。然而，在 KO 小鼠中 ATP2B4 的表达增加。KO 小鼠培养的血管平滑肌细胞不仅在基础状态下，而且在苯肾上腺素刺激状态下，细胞内钙离子浓度均增加。此外，KO 小鼠股动脉血管环中苯肾上腺素诱导的血管收缩明显增加。这些结果表明，ATP2B1 通过改变血管平滑肌细胞中的钙处理和血管收缩在调节血压方面发挥重要作用。
