Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways

Shukuan Ling, Manjyot Nanhwan, Jinqiao Qian, Monica Kodakandla, Alexander C. Castillo, Bejoy Thomas, Hongju Liu, Yumei Ye

Research output: Contribution to journalArticle

28 Citations (Scopus)

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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)127-136
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume65
DOIs
StatePublished - Dec 2013

Fingerprint

MicroRNAs
Hypertension
Growth Factor Receptors
Salts
Insulin
Nebivolol
Aorta
Inbred Dahl Rats
Adrenergic Antagonists
Atenolol
Microarray Analysis
Luciferases
Phosphoric Monoester Hydrolases
Adrenergic Receptors
Antihypertensive Agents
Blood Vessels
Oxidative Stress
Up-Regulation
Down-Regulation
Chromosomes

Keywords

  • β1 receptors
  • β3 receptors
  • Arterial dysfunction
  • Hypertension
  • MicroRNA
  • Vascular remodeling

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways. / Ling, Shukuan; Nanhwan, Manjyot; Qian, Jinqiao; Kodakandla, Monica; Castillo, Alexander C.; Thomas, Bejoy; Liu, Hongju; Ye, Yumei.

In: Journal of Molecular and Cellular Cardiology, Vol. 65, 12.2013, p. 127-136.

Research output: Contribution to journalArticle

Ling, Shukuan ; Nanhwan, Manjyot ; Qian, Jinqiao ; Kodakandla, Monica ; Castillo, Alexander C. ; Thomas, Bejoy ; Liu, Hongju ; Ye, Yumei. / Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways. In: Journal of Molecular and Cellular Cardiology. 2013 ; Vol. 65. pp. 127-136.
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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. Methods and 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.",
keywords = "β1 receptors, β3 receptors, Arterial dysfunction, Hypertension, MicroRNA, Vascular remodeling",
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T1 - Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways

AU - Ling, Shukuan

AU - Nanhwan, Manjyot

AU - Qian, Jinqiao

AU - Kodakandla, Monica

AU - Castillo, Alexander C.

AU - Thomas, Bejoy

AU - Liu, Hongju

AU - Ye, Yumei

PY - 2013/12

Y1 - 2013/12

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - β1 receptors

KW - β3 receptors

KW - Arterial dysfunction

KW - Hypertension

KW - MicroRNA

KW - Vascular remodeling

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