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- W3175618757 abstract "Minocycline is an FDA-approved tetracycline antibiotic that exerts anti-inflammatory and anti-apoptotic effects independent of its bactericidal activity. For example, it attenuates neointima formation after arterial injury and atherosclerotic plaque development in an animal model of diet-induced atherosclerosis via inhibition of smooth muscle cell (SMC) proliferation and migration; however, the molecular mechanisms underlying this inhibition are not completely known. Here we investigated whether minocycline inhibits PDGF-BB-induced primary human aortic SMC (HASMC) proliferation and migration in vitro. Our results show that PDGF-BB stimulates proliferation (~2.92-fold, P<0.05) and migration (~1.8-fold, P<0.05) of HASMC via a redox-sensitive mechanism involving NOX2 (inhibited by gp91dstat) and NOX4 (inhibited by GKT137831). Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs (RECK) is a cell surface expressed, membrane anchored matrix metalloproteinase inhibitor. For the first time, our results show that PDGF-BB downregulates RECK expression in a time-dependent manner (by ~80% at 6 h, n=3, P<0.01), but induces miR-221 and miR-222 expression (~1.8-fold and ~2.23-fold, respectively). The reporter assays revealed that both miRs bind the 3′UTR of RECK mRNA, inhibiting its expression by ~50% (P<0.01). Supporting these observations, transduction of miR-221 or miR-222 mimics suppress RECK expression, but their antagomirs reverse PDGF-BB-induced inhibition of HASMC proliferation and migration. Further investigations revealed that PDGF-BB activates the redox-sensitive nuclear transcription factors NF-kB and AP-1 in HASMC, and shRNA directed against the AP-1 subunit c-Jun and the p65 subunit of NF-kB each inhibit PDGF-BB-induced miR-221 or miR-222 expression, suggesting that PDGF-BB suppresses RECK expression in HASMC in part via AP-1- and NF-kB-dependent miR-221 and miR-222 induction. Notably, minocycline increases RECK expression dose-dependently within the therapeutic dose of 1–100 μM, and inhibits PDGF-BB-induced HASMC proliferation and migration. Intriguingly, silencing RECK reverses the inhibitory effects of minocycline on PDGF-BB-induced migration and proliferation. Together, these results demonstrate that PDGF-BB downregulates RECK expression in HASMC via AP-1- and NF-kB-dependent miR-221 and miR-222 induction, and minocycline reverses PDGF-BB-induced ROS generation, miR-221 and miR-222 induction, and RECK suppression. These findings suggest that the induction of RECK is one of the mechanisms by which minocycline exerts vasculoprotective effects. Support or Funding Information NIH R01-HL-070241 (PD)VA Merit Award I01-BX002255 (BC) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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- W3175618757 date "2018-04-01" @default.
- W3175618757 modified "2023-10-14" @default.
- W3175618757 title "Minocycline Inhibits PDGF‐BB‐induced Human Aortic Smooth Muscle Cell Proliferation and Migration via Induction of RECK" @default.
- W3175618757 doi "https://doi.org/10.1096/fasebj.2018.32.1_supplement.676.3" @default.
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