| First Author | Li DJ | Year | 2019 |
| Journal | Br J Pharmacol | Volume | 176 |
| Issue | 22 | Pages | 4388-4401 |
| PubMed ID | 30270436 | Mgi Jnum | J:298485 |
| Mgi Id | MGI:6480171 | Doi | 10.1111/bph.14506 |
| Citation | Li DJ, et al. (2019) Nicotinic ACh receptor alpha7 inhibits PDGF-induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3. Br J Pharmacol 176(22):4388-4401 |
| abstractText | BACKGROUND AND PURPOSE: PDGF-BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor alpha7 subtype (alpha7nAChR) on PDGF-BB-induced proliferation and migration in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH: PNU-282987, a selective alpha7nAChR pharmacological agonist, was used to activate alpha7nAChR. The influences of alpha7nAChR activation on PDGF-BB-induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro-migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. KEY RESULTS: PDGF-BB induced pronounced migration and proliferation of VSMCs. Activation of alpha7nAChRs by PNU-282987 blocked PDGF-BB-induced migration but not proliferation in wild-type (WT) VSMCs, whereas this effect was absent in alpha7nAChR-knockout VSMCs. Accordingly, PNU-282987 attenuated PDGF-BB-induced phosphorylation of FAK(Tyr397) and Src(Tyr416) in WT VSMCs. Mechanistically, PNU-282987 suppressed PDGF-BB-induced oxidative stress, as demonstrated by the alterations in ROS, H2 O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine or shRNA-mediated SIRT3 knockdown abolished the inhibitory effect of PNU-282987. PNU-282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU-282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU-282987 corrected the PDGF-BB-induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. CONCLUSIONS: Pharmacological activation of alpha7nAChRs inhibits PDGF-BB-induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for alpha7nAChRs in mitochondria biology and PDGF-related diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc. |
