title: MicroRNA changes in rat mesentery and serum associated with drug-induced vascular injury.
abstract: Regulatory miRNAs play a role in vascular biology and are involved in biochemical and molecular pathways dysregulated during vascular injury. Collection and integration of functional miRNA data into these pathways can provide insight into pathogenesis at the site of injury; the same technologies applied to biofluids may provide diagnostic or surrogate biomarkers. miRNA was analyzed from mesentery and serum from rats given vasculotoxic compounds for 4 days. Fenoldopam, dopamine and midodrine each alter hemodynamics and are associated with histologic evidence of vascular injury, while yohimbine is vasoactive but does not cause histologic evidence of vascular injury in rat. There were 38 and 35 miRNAs altered in a statistically significant manner with a fold change of 2 or greater in mesenteries of fenoldopam- and dopamine-dosed rats, respectively, with 9 of these miRNAs shared. 10 miRNAs were altered in rats given midodrine; 6 were shared with either fenoldopam or dopamine. In situ hybridization demonstrated strong expression and co-localization of miR-134 in affected but not in adjacent unaffected vessels. Mesenteric miRNA expression may provide clarity or avenues of research into mechanisms involved in vascular injury once the functional role of specific miRNAs becomes better characterized. 102 miRNAs were altered in serum from rats with drug-induced vascular injury. 10 miRNAs were commonly altered in serum from dopamine and either fenoldopam or midodrine dosed rats; 18 of these 102 were also altered in mesenteries from rats with drug-induced vascular injury, suggesting their possible utility as peripheral biomarkers.
authors.affiliation: Safety Assessment, Pathology, GlaxoSmithKline, King of Prussia, PA 19406, USA. Roberta.A.Thomas@gsk.com
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Thomas
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Scicchitano
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Mirabile
authors.forename: Nancy T
authors.initials: NT
authors.lastname: Chau
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
authors.forename: Heath C
authors.initials: HC
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D008643:Mesentery / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008879:Midodrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D035683:MicroRNAs; D008879:Midodrine; D018818:Fenoldopam; D004298:Dopamine