7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity
7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity
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α7 烟碱乙酰胆碱受体通过提高烟酰胺腺嘌呤二核苷酸依赖性 SIRT1 活性来缓解血管紧张素 II 诱导的血管平滑肌细胞衰老。
DOI：
10.1161/atvbaha.116.307157
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发表时间：
2016-08-01
影响因子：
8.7
通讯作者：
Shen, Fu-Ming
中科院分区：
文献类型：
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作者：
Li, Dong-Jie;Huang, Fang;Shen, Fu-Ming
目的7：烟碱乙酰胆碱受体（nicotinic acetylcholine receptor, 7nAChR）是nAChR的一个亚型，已被报道参与高血压终末器官损害。在这项研究中，我们测试了7nAChR在血管紧张素II （Ang II）诱导的血管平滑肌细胞（VSMCs）衰老中的作用。方法与结果7nAChR的表达不受Angⅱ的影响。Ang II在啮齿动物和人类VSMCs中诱导了显着的衰老表型，包括衰老相关的-半乳糖苷酶活性增加，H2A磷酸化。X-Ser139, Chk1（Ser317）磷酸化，复制减少，增殖细胞核抗原下调。选择性激动剂PNU-282987激活7nAChR可阻断Ang ii诱导的VSMCs衰老。此外，PNU-282987治疗可以减轻野生型小鼠Ang II输注诱导的VSMC衰老，但对7nAChR（-/-）小鼠没有作用。PNU-282987降低了angii增强的活性氧、脂质过氧化、NADPH氧化酶1、NADPH氧化酶4和p22（phox）在野生型培养的VSMCs中的表达，但在7nAChR（-/-）小鼠中无此作用。此外，PNU-282987减少了Ang ii诱导的衰老信号通路，包括p53、乙酰型p53、p21和p16（INK4a）。最后，虽然PNU-282987激活7nAChR并不影响Ang ii诱导的SIRT1下调，但它显著增加了细胞内NAD（+）水平，从而以amp依赖性蛋白激酶不依赖的方式增强了SIRT1活性。通过敲低SIRT1或SIRT1抑制剂EX527去除SIRT1可消除7nAChR对Ang II的抗衰老作用。我们的研究结果表明，7nAChR的激活通过促进NAD(+)-SIRT1通路减轻了Ang ii诱导的VSMC衰老，提示7nAChR可能是治疗Ang ii相关血管衰老疾病的潜在治疗靶点。
Objective 7 nicotinic acetylcholine receptor (7nAChR) is a subtype of nAChR and has been reported to be involved in hypertension end-organ damage. In this study, we tested the role of 7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs).Approach and Results Expression of 7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated -galactosidase activity, phosphorylation of H2A.X-Ser139, phosphorylation of Chk1(Ser317), reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of 7nAChR with a selective agonist PNU-282987 blocked Ang II-induced senescence in cultured VSMCs. Moreover, PNU-282987 treatment attenuated the Ang II infusion-induced VSMC senescence in wild-type but not in 7nAChR(-/-) mice. PNU-282987 reduced the Ang II-enhanced reactive oxygen species, lipid peroxidation, and the expression of NADPH oxidase 1, NADPH oxidase 4, and p22(phox) in cultured VSMCs isolated from wild-type but not in 7nAChR(-/-) mice. Furthermore, PNU-282987 diminished Ang II-induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16(INK4a). Finally, although 7nAChR activation by PNU-282987 did not affect the Ang II-induced downregulation of sirtuin 1 (SIRT1), it significantly increased intracellular NAD(+) levels, and thereby enhanced SIRT1 activity in an AMP-dependent protein kinase-independent manner. Depletion of SIRT1 by knockdown or SIRT1 inhibitor EX527 abrogated the antisenescence effect of 7nAChR against Ang II.Conclusions Our results demonstrate that activation of 7nAChR alleviates Ang II-induced VSMC senescence through promoting NAD(+)-SIRT1 pathway, suggesting that 7nAChR may be a potential therapeutic target for the treatment of Ang II-associated vascular aging disorders.