Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling

Roelien A.M. Meijering, Marit Wiersma, Deli Zhang, Eva A.H. Lanters, Femke Hoogstra-Berends, Jetse Scholma, Sander Diks, Xiao Yan Qi, Natasja M.S. de Groot, Stanley Nattel, Robert H. Henning, Bianca J.J.M. Brundel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Dysregulation of protein kinase–mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases. Objective: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing). Methods: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases. Results: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array. Conclusion: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.

Original languageEnglish
Pages (from-to)1708-1716
Number of pages9
JournalHeart Rhythm
Volume15
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Cite this

Meijering, Roelien A.M. ; Wiersma, Marit ; Zhang, Deli ; Lanters, Eva A.H. ; Hoogstra-Berends, Femke ; Scholma, Jetse ; Diks, Sander ; Qi, Xiao Yan ; de Groot, Natasja M.S. ; Nattel, Stanley ; Henning, Robert H. ; Brundel, Bianca J.J.M. / Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling. In: Heart Rhythm. 2018 ; Vol. 15, No. 11. pp. 1708-1716.
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title = "Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling",
abstract = "Background: Dysregulation of protein kinase–mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases. Objective: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing). Methods: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases. Results: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array. Conclusion: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.",
keywords = "Akt, Atrial fibrillation, Cardiomyocytes, CDK, Kinases, Kinome array, SRC",
author = "Meijering, {Roelien A.M.} and Marit Wiersma and Deli Zhang and Lanters, {Eva A.H.} and Femke Hoogstra-Berends and Jetse Scholma and Sander Diks and Qi, {Xiao Yan} and {de Groot}, {Natasja M.S.} and Stanley Nattel and Henning, {Robert H.} and Brundel, {Bianca J.J.M.}",
year = "2018",
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Meijering, RAM, Wiersma, M, Zhang, D, Lanters, EAH, Hoogstra-Berends, F, Scholma, J, Diks, S, Qi, XY, de Groot, NMS, Nattel, S, Henning, RH & Brundel, BJJM 2018, 'Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling' Heart Rhythm, vol. 15, no. 11, pp. 1708-1716. https://doi.org/10.1016/j.hrthm.2018.06.014

Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling. / Meijering, Roelien A.M.; Wiersma, Marit; Zhang, Deli; Lanters, Eva A.H.; Hoogstra-Berends, Femke; Scholma, Jetse; Diks, Sander; Qi, Xiao Yan; de Groot, Natasja M.S.; Nattel, Stanley; Henning, Robert H.; Brundel, Bianca J.J.M.

In: Heart Rhythm, Vol. 15, No. 11, 01.11.2018, p. 1708-1716.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Application of kinomic array analysis to screen for altered kinases in atrial fibrillation remodeling

AU - Meijering, Roelien A.M.

AU - Wiersma, Marit

AU - Zhang, Deli

AU - Lanters, Eva A.H.

AU - Hoogstra-Berends, Femke

AU - Scholma, Jetse

AU - Diks, Sander

AU - Qi, Xiao Yan

AU - de Groot, Natasja M.S.

AU - Nattel, Stanley

AU - Henning, Robert H.

AU - Brundel, Bianca J.J.M.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: Dysregulation of protein kinase–mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases. Objective: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing). Methods: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases. Results: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array. Conclusion: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.

AB - Background: Dysregulation of protein kinase–mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases. Objective: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing). Methods: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases. Results: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array. Conclusion: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.

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KW - Atrial fibrillation

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KW - CDK

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