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 wildtype 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

Killing Me Unsoftly

“…A study by Li, et al tested the role of α7nAChR in Ang II–induced senescence of VSMCs and found 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. 71 Interestingly, another ATVB publication by Gardner, et al suggested that senescent VSMCs may be active participants in CVD processes and assume a pro-inflammatory state and secrete factors that promote chemotaxis of mononuclear cells in vitro and in vivo and that release active MMP-9, secrete less collagen, and prime endothelial cells and VSMCs to a pro-inflammatory state. 72 And while this was established in a model of atherosclerosis, whether this VSMC phenotype plays a direct role in arterial stiffness remains to be investigated.…”

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

“…Nicotine might lead to suppressed apoptosis and cisplatin resistance via α5nAChR/AKT signaling [112]. In addition, α7nAChR may be implicated in the NAD + /SIRT1 pathway, which promotes chemotherapeutic drug resistance [131]. Nicotine/α9nAChR signaling can reduce apoptotic pathways [116].…”

“…The SIRT1-PARP-1 axis plays a critical role in the regulation of cigarette smoke-induced autophagy and has notable implications for understanding the mechanisms of cigarette smoke-induced cell death and senescence [130]. α7nAChR-SIRT1 axis activation alleviates angiotensin II-induced VSMC senescence [131]. Recent studies have focused on the biological functions of SIRT1 in metabolic diseases, cancer, aging and cellular senescence, inflammatory signaling in response to environmental stress, and cell survival [132][133][134][135].…”

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

“…Ang II stimulation also induces senescence of vascular cells (Li et al, 2016;Kunieda et al, 2006). Moreover, Ang II is a potent mediator of oxidative stress and oxidant signaling leading to vascular premature senescence (Andrés, 2014).…”