First Author | Li DJ | Year | 2016 |
Journal | Arterioscler Thromb Vasc Biol | Volume | 36 |
Issue | 8 | Pages | 1566-76 |
PubMed ID | 27339462 | Mgi Jnum | J:246227 |
Mgi Id | MGI:5920427 | Doi | 10.1161/ATVBAHA.116.307157 |
Citation | Li DJ, et al. (2016) alpha7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity. Arterioscler Thromb Vasc Biol 36(8):1566-76 |
abstractText | OBJECTIVE: alpha7 nicotinic acetylcholine receptor (alpha7nAChR) 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 alpha7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: Expression of alpha7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated beta-galactosidase activity, phosphorylation of H2A.X(Ser139), phosphorylation of Chk1(Ser317), reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of alpha7nAChR 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 alpha7nAChR(-/-) 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 alpha7nAChR(-/-) mice. Furthermore, PNU-282987 diminished Ang II-induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16(INK4a). Finally, although alpha7nAChR 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 alpha7nAChR against Ang II. CONCLUSIONS: Our results demonstrate that activation of alpha7nAChR alleviates Ang II-induced VSMC senescence through promoting NAD(+)-SIRT1 pathway, suggesting that alpha7nAChR may be a potential therapeutic target for the treatment of Ang II-associated vascular aging disorders. |