title: Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways.
abstract: BACKGROUND
  Dysregulation of microRNAs (miRNAs) in arterial dysfunction and hypertension has not been extensively investigated yet. This project determined the effects of two anti-hypertensive β1 adrenergic selective blockers on miRNA expression in the Dahl Salt Sensitive (DSS) hypertensive rat model.
  
  
  RESULTS
  Microarray analysis showed that a set of miRNAs is differently expressed in the aorta of high salt (HS) treated rats with miR-320 increased and miR-26b and -21 decreased. All of these changes were reverted to normal by nebivolol (NEB, a β1 selective-blocker and β3 activator). The selective β3-adrenoceptor antagonist S-(-)-cyanopindolol (Syc) counteracted the effect of NEB on these miRNAs. Atenolol (ATN, a pure β1-blocker) combined with specific β3 agonist BRL37344 restored the expression of all three miRNAs, similar to NEB, while ATN alone had only a partial effect on miR-320 expression. Computational analysis found Insulin Growth Factor-1 Receptor (IGF1R) as a putative target of miR-320, and Phosphatase and tensin homolog on chromosome ten (PTEN) as a putative target of miR-26b and -21. The targets were verified by luciferase reporter assays. Inhibition of miR-320 by an antisense inhibitor or NEB increased IGF1R expression, while miR-320 overexpression reversed the effect of NEB. Overexpression of miR-26b or -21 or NEB decreased PTEN levels, while inhibition of miR-26b or -21 attenuated the effect of NEB. HS diet induced downregulation of IGF1R and upregulation of PTEN in the aorta. NEB normalized the aberrant expression of IGF1R and PTEN and also improved the impairment of vascular AKT/eNOS signaling. Moreover, both NEB and ATN showed to have protective effects on salt-induced hypertension, oxidative stress, and vascular remodeling. NEB had a greater effect than ATN.
  
  
  CONCLUSIONS
  Our data supports a differential miRNA expression profile in salt-induced hypertension. Manipulation of dysregulated miRNAs by β-blockers may substantially induce alterations of gene expression and prevent arterial dysfunction and remodeling.
authors.affiliation: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Shukuan
authors.initials: S
authors.lastname: Ling
authors.forename: Manjyot
authors.initials: M
authors.lastname: Nanhwan
authors.forename: Jinqiao
authors.initials: J
authors.lastname: Qian
authors.forename: Monica
authors.initials: M
authors.lastname: Kodakandla
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Castillo
authors.forename: Bejoy
authors.initials: B
authors.lastname: Thomas
authors.forename: Hongju
authors.initials: H
authors.lastname: Liu
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001262:Atenolol / Q000494:pharmacology; D064752:Atrial Remodeling / Q000187:drug effects / Q000235:genetics*; D001578:Benzopyrans / Q000494:pharmacology; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003094:Collagen; D004983:Ethanolamines / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068577:Nebivolol; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D017673:Sodium Chloride, Dietary
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D035683:MicroRNAs; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D017673:Sodium Chloride, Dietary; D000068577:Nebivolol; D001262:Atenolol; D003094:Collagen; D008156:Luciferases; D017526:Receptor, IGF Type 1; D051059:PTEN Phosphohydrolase
keywords: Arterial dysfunction; Hypertension; MicroRNA; Vascular remodeling; β1 receptors; β3 receptors