α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity.

Abstract

OBJECTIVE:

α7 nicotinic acetylcholine receptor (α7nAChR) 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 α7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs).

APPROACH AND RESULTS:

Expression of α7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated β-galactosidase activity, phosphorylation of H2A.X(Ser139), phosphorylation of Chk1(Ser317), reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of α7nAChR 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 α7nAChR(-/-) 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 α7nAChR(-/-) mice. Furthermore, PNU-282987 diminished Ang II-induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16(INK4a). Finally, although α7nAChR 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 α7nAChR against Ang II.

CONCLUSIONS:

Our results demonstrate that activation of α7nAChR alleviates Ang II-induced VSMC senescence through promoting NAD(+)-SIRT1 pathway, suggesting that α7nAChR may be a potential therapeutic target for the treatment of Ang II-associated vascular aging disorders.

• Authors: Dong-Jie Li, Fang Huang, Min Ni, Hui Fu, Liang-Sheng Zhang, Fu-Ming Shen
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 36 Issue 8 Pg. 1566-76 (08 2016) ISSN: 1524-4636 [Electronic] United States
• PMID: 27339462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Chrna7 protein, human
• Chrna7 protein, mouse
• Chrna7 protein, rat
• Histone Deacetylase Inhibitors
• Nicotinic Agonists
• alpha7 Nicotinic Acetylcholine Receptor
• NAD
• Angiotensin II
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirt1 protein, rat
• Sirtuin 1

Topics

• Angiotensin II (toxicity)
• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cellular Senescence (drug effects)
• Disease Models, Animal
• Genotype
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hypertension (chemically induced, enzymology, genetics)
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, enzymology, pathology)
• NAD (metabolism)
• Nicotinic Agonists (pharmacology)
• Oxidative Stress (drug effects)
• Phenotype
• RNA Interference
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Sirtuin 1 (antagonists & inhibitors, genetics, metabolism)
• Time Factors
• Transfection
• Up-Regulation
• alpha7 Nicotinic Acetylcholine Receptor (agonists, deficiency, genetics, metabolism)