β-adrenergic receptor/β-arrestin-mediated microRNA maturation regulatory network: A new player in cardioprotective signaling

Hdl Handle:
http://hdl.handle.net/10675.2/621683
Title:
β-adrenergic receptor/β-arrestin-mediated microRNA maturation regulatory network: A new player in cardioprotective signaling
Authors:
Teoh, Jian Peng
Abstract:
Chronic treatment with the β-blocker carvedilol (Carv) has been shown to reduce established maladaptive left ventricle (LV) hypertrophy and to improve LV function in experimental heart failure. However, the detailed mechanisms by which carvedilol improves LV failure are poorly understood. We previously showed that carvedilol is a β-arrestin-biased β1-adrenergic receptor ligand, which activates cellular pathways through β-arrestins in the heart independent of G protein-mediated second messenger signaling, a concept known as biased signaling. Here, we sought to (i) identify the effects of Carv on LV gene expression on a genome-wide basis and (ii) investigate whether Carv could regulate novel miR expression/biogenesis, thereby providing a novel mechanism for its cardioprotective effects. Gene expression profiling analysis revealed that subsets of genes are differentially expressed after Carv treatment. Further analysis categorized these genes into pathways involved in tight junction, cardiac response to malaria, viral myocarditis, glycosaminoglycan biosynthesis, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Genes encoding proteins in the tight junction, malaria, and viral myocarditis pathways were upregulated in the LV by Carv, while genes encoding proteins in the glycosaminoglycan biosynthesis and ARVC pathways were downregulated by Carv. In addition, our findings also revealed that Carv indeed upregulates 3 mature miRs, but not their pre-miRs and pri-miRs, in a β-arrestin1/2-dependent manner. Interestingly, Carv-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2AR and β1AR, respectively. Mechanistically, β-arrestins regulate maturation of 3 newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer complex as well as two RNA binding proteins (hnRNPK and dyskerin) on three pre-miRs. Cardiac cell approaches uncover that β-miRs act as gatekeepers of cardiac cell function by repressing deleterious targets. Our findings indicate a novel role for βAR-mediated β-arrestin signaling activated by Carv in miR maturation, which may be linked to its protective mechanism. Altogether, our findings indicate that (i) the gene expression changes may reflect the molecular mechanisms that underlie the functional benefits of Carv therapy and (ii) the novel role for βAR-mediated β-arrestin signaling activated by Carv in miR maturation, which may be linked to its protective mechanism.
Affiliation:
Department of Biochemistry and Molecular Biology / Cancer Center
Issue Date:
1
URI:
http://hdl.handle.net/10675.2/621683
Type:
Dissertation
Description:
The file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus. Record is embargoed until 1/25/2019
Appears in Collections:
Theses and Dissertations; Department of Biochemistry and Molecular Biology Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorTeoh, Jian Peng-
dc.date.accessioned2018-01-25T23:23:38Z-
dc.date.available2018-01-25T23:23:38Z-
dc.date.issued1/25/2018-
dc.identifier.urihttp://hdl.handle.net/10675.2/621683-
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus. Record is embargoed until 1/25/2019en
dc.description.abstractChronic treatment with the β-blocker carvedilol (Carv) has been shown to reduce established maladaptive left ventricle (LV) hypertrophy and to improve LV function in experimental heart failure. However, the detailed mechanisms by which carvedilol improves LV failure are poorly understood. We previously showed that carvedilol is a β-arrestin-biased β1-adrenergic receptor ligand, which activates cellular pathways through β-arrestins in the heart independent of G protein-mediated second messenger signaling, a concept known as biased signaling. Here, we sought to (i) identify the effects of Carv on LV gene expression on a genome-wide basis and (ii) investigate whether Carv could regulate novel miR expression/biogenesis, thereby providing a novel mechanism for its cardioprotective effects. Gene expression profiling analysis revealed that subsets of genes are differentially expressed after Carv treatment. Further analysis categorized these genes into pathways involved in tight junction, cardiac response to malaria, viral myocarditis, glycosaminoglycan biosynthesis, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Genes encoding proteins in the tight junction, malaria, and viral myocarditis pathways were upregulated in the LV by Carv, while genes encoding proteins in the glycosaminoglycan biosynthesis and ARVC pathways were downregulated by Carv. In addition, our findings also revealed that Carv indeed upregulates 3 mature miRs, but not their pre-miRs and pri-miRs, in a β-arrestin1/2-dependent manner. Interestingly, Carv-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2AR and β1AR, respectively. Mechanistically, β-arrestins regulate maturation of 3 newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer complex as well as two RNA binding proteins (hnRNPK and dyskerin) on three pre-miRs. Cardiac cell approaches uncover that β-miRs act as gatekeepers of cardiac cell function by repressing deleterious targets. Our findings indicate a novel role for βAR-mediated β-arrestin signaling activated by Carv in miR maturation, which may be linked to its protective mechanism. Altogether, our findings indicate that (i) the gene expression changes may reflect the molecular mechanisms that underlie the functional benefits of Carv therapy and (ii) the novel role for βAR-mediated β-arrestin signaling activated by Carv in miR maturation, which may be linked to its protective mechanism.en
dc.subjectβ-arrestin-biased β-adrenergic receptor signalingen
dc.subjectCarvedilolen
dc.subjectCell Signalingen
dc.subjectHeart Diseaseen
dc.subjectMicroRNA Biogenesisen
dc.subjectRNA Binding Proteinsen
dc.titleβ-adrenergic receptor/β-arrestin-mediated microRNA maturation regulatory network: A new player in cardioprotective signalingen
dc.typeDissertationen
dc.contributor.departmentDepartment of Biochemistry and Molecular Biology / Cancer Centeren
dc.language.rfc3066en-
dc.date.updated2018-01-25T23:23:38Z-
dc.description.advisorKim, Il-manen
dc.description.committeeSu, Huabo; Johnson, John; Weintraub, Neal; Tang, Yaoliangen
dc.description.degreeDoctor of Philosophy with a Major in Biochemistry and Center Biologyen
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