Coupling factor 6 enhances Src-mediated responsiveness to angiotensin II in resistance arterioles and cells.
Coupling factor 6 enhances Src-mediated responsiveness to angiotensin II in resistance arterioles and cells.
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DOI：
10.1093/cvr/cvn356
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发表时间：
2008-12
影响因子：
10.8
通讯作者：
T. Osanai;H. Tomita;M. Kushibiki;M. Yamada;Makoto Tanaka;Toshihiro Ashitate;Takashi Echizen;C. Katoh;K. Magota;K. Okumura
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文献类型：
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作者：
T. Osanai;H. Tomita;M. Kushibiki;M. Yamada;Makoto Tanaka;Toshihiro Ashitate;Takashi Echizen;C. Katoh;K. Magota;K. Okumura
目的偶联因子6（CF 6）通过抑制内皮细胞生成前列环素诱导高血压。然而，CF 6在阻力小动脉血管平滑肌细胞（VSMCs）中的细胞内信号传导与血管收缩直接相关，尚未确定。在这里，我们研究了直接影响外源性CF 6对Ca 2+信号在培养的VSMCs和内源性CF 6在体内的作用，使用CF 6转基因（TG）小鼠的高血压的发生。方法和结果CF 6通过硝苯地平敏感性钙通道诱导VSMCs细胞内游离钙浓度（[Ca 2 +]i）的双相增加，并在更大程度上增强血管紧张素II诱导的自发性高血压大鼠（SHR）VSMCs [Ca 2 +]i峰电位相。在从表现出高血压的CF 6-TG小鼠获得的肠系膜小动脉中，与野生型小鼠相比，血管紧张素II诱导的血管收缩增强，并且其增强被抗CF 6抗体消除。用酪氨酸激酶c-Src抑制剂PP 1预处理，阻断CF 6诱导的VSMC中Ca 2+信号的增加和TG小鼠的血管收缩。CF 6受体是三磷酸腺苷（ATP）合成酶的F1马达，在SHR中具有较高的亲和力。CF 6通过激活ATP酶活性降低细胞内pH，并导致c-Src在更大程度上激活SHR来源的VSMCs。结论CF 6通过激活c-Src直接增强VSMCs内Ca 2+信号和肠系膜小动脉网收缩血管而引起高血压。
AIMS Coupling factor 6 (CF6) induces hypertension by attenuating the endothelial generation of prostacyclin. However, intracellular signalling of CF6 in the resistance arteriole vascular smooth muscle cells (VSMCs) that are directly related to vasoconstriction has not been determined. Here we investigated the direct effect of exogenous CF6 on Ca2+ signalling in cultured VSMCs and the in vivo role of endogenous CF6 in the genesis of hypertension using CF6 transgenic (TG) mice. METHODS AND RESULTS CF6 induced a monophasic increase in the intracellular free Ca2+ concentration ([Ca2+]i) through nifedipine-sensitive Ca2+ channels in A7r5 cells, a cell line of VSMCs, and enhanced the angiotensin II-induced spike phase of [Ca2+]i to a greater degree in VSMCs derived from spontaneously hypertensive rats (SHRs). In the mesenteric arterioles obtained from CF6-TG mice that manifested hypertension, angiotensin II-induced vasoconstriction was enhanced, compared with wild-type mice, and its enhancement was abolished by an anti-CF6 antibody. Pre-treatment with PP1, a tyrosine kinase c-Src inhibitor, blocked CF6-induced increase in Ca2+ signalling in VSMCs and vasoconstriction in TG mice. The receptor of CF6 was F1 motor of adenosine triphosphate (ATP) synthase with a higher affinity in SHRs. CF6 decreased intracellular pH via activation of ATPase activity and led to c-Src activation to a greater degree in SHR-derived VSMCs. CONCLUSION CF6 causes hypertension by directly enhancing Ca2+ signalling in VSMCs and vasoconstriction in the mesenteric arteriolar network via c-Src activation.