Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Abstract

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 α7 subtype (α7nAChR) on PDGF‐BB‐induced proliferation and migration in vascular smooth muscle cells (VSMCs). Experimental Approach PNU‐282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR 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 α7nAChRs by PNU‐282987 blocked PDGF‐BB‐induced migration but not proliferation in wild‐type (WT) VSMCs, whereas this effect was absent in α7nAChR‐knockout VSMCs. Accordingly, PNU‐282987 attenuated PDGF‐BB‐induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU‐282987 suppressed PDGF‐BB‐induced oxidative stress, as demonstrated by the alterations in ROS, H2O2 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 α7nAChRs inhibits PDGF‐BB‐induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs 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

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