Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II
Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II
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DOI：
10.1111/fcp.12111
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发表时间：
2015-06-01
影响因子：
2.9
通讯作者：
Yang, Qing
中科院分区：
文献类型：
--
作者：
Jiao, Yuhang;Yang, Qing
血管紧张素II可以下调心钠素与大鼠血管平滑肌细胞（VSMC）的结合，但其机制尚不清楚。由于蛋白激酶C（PKC）模拟物佛波酯肉豆蔻酸酯醋酸酯（PMA）可以使利尿钠肽清除受体（NPR-C）mRNA不稳定，血管紧张素II激活VSMC中的几种PKC亚型，我们假设血管紧张素II治疗降低NPR-C mRNA的稳定性，并通过PKC发挥这种作用。这项研究表明，血管紧张素II诱导NPR-C的时间和浓度依赖性下调，这是完全抑制血管紧张素II I型受体阻滞剂氯沙坦。与单独抑制RNA合成相比，暴露于100 nm血管紧张素II的VSMCs在6 h内NPR-C mRNA的消失率几乎增加了一倍。然而，这种对血管紧张素II的反应并没有被PKC抑制剂白屈菜红碱或通过预先将细胞暴露于PMA 48小时来消耗PKC而减弱。酪氨酸激酶、磷脂酶C或丝裂原活化蛋白激酶激酶的抑制剂也未能逆转血管紧张素II的作用。我们的结论是，至少有两个不同的近端信号通路，一个参与和一个独立的佛波酯敏感的蛋白激酶C，导致下调NPR-C基因表达的不稳定的mRNA。
Angiotensin II can downregulate atrial natriuretic peptide binding to rat vascular smooth muscle cells (VSMCs), but the mechanism is not known. Because protein kinase C (PKC) mimetic phorbol myristate acetate (PMA) can destabilize natriuretic peptide clearance receptor (NPR-C) mRNA and angiotensin II activates several PKC isoforms in VSMCs, we hypothesized that angiotensin II treatment decreases NPR-C mRNA stability and exerts this effect through PKC. This study demonstrated that angiotensin II induced time- and concentration-dependent downregulation of NPR-C, which was completely inhibited by an angiotensin II type I receptor blocker losartan. NPR-C mRNA disappearance rate over 6h was nearly doubled by exposure of VSMCs to 100nm angiotensin II, compared with that observed after inhibition of RNA synthesis alone. However, this response to angiotensin II was undiminished by the PKC inhibitor chelerythrine, or by depletion of PKC by prior exposure of cells to PMA for 48h. Inhibitors of tyrosine kinases, phospholipase C, or mitogen-activated protein kinase kinase also failed to reverse the angiotensin II effect. We conclude that at least two distinct proximal signaling pathways, one involved and one independent of phorbol ester-sensitive protein kinase C, lead to downregulation of NPR-C gene expression by destabilizing its mRNA.