Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.
Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.
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DOI：
10.1371/journal.pone.0049915
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wu LL
中科院分区：
文献类型：
--
作者：
Li L;Zhang ZG;Lei H;Wang C;Wu LP;Wang JY;Fu FY;Zhu WG;Wu LL
脂联素是一种丰富的脂肪组织来源的蛋白质，对心血管疾病具有保护作用。脂联素受体（AdipoR1 和 AdipoR2）介导脂联素对心血管系统的有益作用。然而，AdipoRs 在心脏重塑中的改变尚未完全阐明。在这里，我们研究了血管紧张素II（AngII）对心脏AdipoRs表达的影响，并探讨了可能的分子机制。 AngII输注给大鼠可引起心脏肥大，降低AdipoR1而非AdipoR2的表达，并减弱腺苷单磷酸激活蛋白激酶和乙酰辅酶A羧化酶的磷酸化，而这些效应均被AngII 1型（AT1）受体阻滞剂氯沙坦逆转。 AngII 降低培养的新生大鼠心肌细胞中 AdipoR1 mRNA 和蛋白的表达，这种作用可以被氯沙坦消除，但不能被 AT2 受体拮抗剂 PD123319 消除。抗氧化剂包括活性氧 (ROS) 清除剂 NAC、NADPH 氧化酶抑制剂夹竹桃麻素、Nox2 抑制剂肽 gp91 ds-tat 和线粒体电子传递链复合物 I 抑制剂鱼藤酮，可减弱 AngII 诱导的 ROS 产生和细胞外信号调节激酶 (ERK) 1/2 的磷酸化。用 NAC、夹竹桃麻素、gp91 ds-tat、鱼藤酮和 ERK1/2 抑制剂 PD98059 预处理可逆转 AngII 降低的 AdipoR1 表达。染色质免疫沉淀测定表明，AngII 引发 c-Myc 募集到 AdipoR1 启动子区域，而 PD98059 减弱了这种作用。此外，氯沙坦、NAC、夹竹桃麻宁、gp91 ds-tat、鱼藤酮和 PD98059 抑制 AngII 诱导的 c-Myc DNA 结合活性。 c-Myc 小干扰 RNA 消除了 AngII 对 AdipoR1 表达的抑制作用。我们的结果表明，AngII 在体内和体外抑制心脏 AdipoR1 的表达，AT1 受体/ROS/ERK1/2/c-Myc 通路是 AngII 诱导的 AdipoR1 下调所必需的。
Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.
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