title: Gene Expression and MicroRNA Expression Analysis in Small Arteries of Spontaneously Hypertensive Rats. Evidence for ER Stress.
abstract: Small arteries are known to develop functional and structural alterations in hypertension. However, the mechanisms of this remodeling are not fully understood. We hypothesized that altered gene expression is associated with the development of hypertension in mesenteric arteries of spontaneously hypertensive rats (SHR). Three sublines of SHR and normotensive Wistar Kyoto rats (WKY) were studied at 6 weeks and 5 months of age. MiRNA and mRNA microarray experiments were performed and analyzed with bioinformatical tools, including Ingenuity Pathway Analysis (IPA). Principal component analysis showed a clear separation in both miRNA and mRNA expression levels between both ages studied, demonstrating strong age-related changes in expression. At the miRNA level, IPA identified differences between SHR and WKY related to metabolic diseases, cellular growth, and proliferation. The mRNAs differentially expressed between SHR and WKY were related to metabolism, cellular movement and proliferation. The most strongly upregulated gene (9.2-fold) was thrombospondin 4 (Thbs4), a protein involved in the endoplasmic reticulum (ER) stress response that activates transcription factor 6α (ATF6α). ATF6α downstream targets were also differentially expressed in SHR vs. WKY. Differential expression of THBS4, the cleaved form of ATF6α, and two of its targets were further confirmed at the protein level by western blot. In summary, these data revealed a number of genes (n = 202) and miRNAs (n = 3) in mesenteric arteries of SHR that had not been related to hypertension previously. The most prominent of these, Thbs4, is related to vascular ER stress that is associated with hypertension.
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palao
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.affiliation: Bioinformatics Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Bioinformatics Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: van Weert
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Arribas
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Gergely
authors.initials: G
authors.lastname: Groma
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ed
authors.initials: E
authors.lastname: vanBavel
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik N T P
authors.initials: EN
authors.lastname: Bakker
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D015536:Down-Regulation / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D019699:Thrombospondins; C101864:thrombospondin 4