title: The SUR2B subunit of rat vascular KATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal.
abstract: ATP-sensitive K(+) (K(ATP)) channels regulate plasma membrane excitability. The Kir6.1/SUR2B isoform of K(ATP) channels is expressed in vascular smooth muscles and plays an important role in vascular tone regulation. This K(ATP) channel is targeted by several reactive species. One of them is methylglyoxal (MGO), which is overly produced with persistent hyperglycemia and contributes to diabetic vascular complications. We have previously found that MGO causes posttranscriptional inhibition of the K(ATP) channel, aggravating vascular tone regulation. Here we show evidence for the underlying molecular mechanisms. We screened microRNA databases and found several candidates. Of them, miR-9a-3p, increased its expression level by ∼240% when the cultured smooth muscle cell line was exposed to micromolar concentrations of MGO. Treatments with exogenous miR-9a-3p downregulated the SUR2B but not Kir6.1 mRNA. Antisense nucleotides of miR-9a-3p alleviated the effects of MGO. Quantitative PCR showed that the targeting sites of the miR-9a-3p were likely to be in the coding region of SUR2B. The effects of miR-9a-3p were mostly eliminated when the potential targeting site in SUR2B was site-specifically mutated. Our functional assays showed that K(ATP) currents were impaired by miR-9a-3p induced with MGO treatment. These results suggest that MGO exposure raises the expression of miR-9a-3p, which subsequently downregulates the SUR2B mRNA, compromising K(ATP) channel function in vascular smooth muscle.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Li
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia cjiang@gsu.edu.
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D054086:KATP Channels / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D064233:Sulfonylurea Receptors / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D035683:MicroRNAs; D064233:Sulfonylurea Receptors; C092520:uK-ATP-1 potassium channel; D011765:Pyruvaldehyde
keywords: ATP-sensitive potassium channel; diabetes; microRNA