title: Nicotine facilitates VSMC dysfunction through a miR-200b/RhoGDIA/cytoskeleton module.
abstract: Nicotine can induce the abnormal migration and proliferation of vascular smooth muscle cells (VSMCs). We have previously shown that cytoskeletal proteins and RhoGDIA, a negative regulator of the Rho GTPase pathway, are involved in the nicotine-induced dysfunction of VSMCs. Here, we found that nicotine can activate the Rho GTPase pathway and induce the synthesis of the cytoskeletal proteins in VSMCs through the activation of intracellular downstream signaling pathways, including targets such as MYPT1, PAK1 and PI3K/AKT. Upon nicotine treatment, the mRNA level of RhoGDIA is increased but protein level is decreased both in vitro and in vivo, which suggested a mechanism of post-translational regulation. By the dual luciferase reporter assay, we identified the microRNA-200b (miR-200b) as a modulator of the behavioural changes of VSMCs in response to nicotine through targeting RhoGDIA directly. Introducing miR-200b inhibitors into cultured VSMCs significantly attenuated cell proliferation and migration. Additionally, we found that hypomethylation in the CpG island shore region of miR-200b was responsible for the nicotine-induced miR-200b up-regulation in VSMCs. The study demonstrates that nicotine facilitates VSMC dysfunction through a miR-200b/RhoGDIA/cytoskeleton module through the hypomethylation of miR-200b promoter and suggests that epigenetic modifications may play an important role in the pathological progression.
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Dongli
authors.initials: D
authors.lastname: Liang
authors.affiliation: Laboratory Animal Center of Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Central laboratory, Shanghai Jiao Tong University affiliated Sixth People's Hospital South Campus, Shanghai, 201400, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Hongqiao international institute of medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, PR China.
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Wangjie
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Lianyun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, PR China.
authors.forename: Meisheng
authors.initials: M
authors.lastname: Shang
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Qiao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D005731:Ganglionic Stimulants / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D005731:Ganglionic Stimulants; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D009538:Nicotine