Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

Stephan R. Künzel; Maximilian Hoffmann; Silvio Weber; Karolina Künzel; Susanne Kämmerer; Mario Günscht; Erik Klapproth; Johanna S.E. Rausch; Mirna S. Sadek; Tomasz Kolanowski; Stefanie Meyer-Roxlau; Christopher Piorkowski; Sems M. Tugtekin; Stefan Rose-John; Xiaoke Yin; Manuel Mayr; Jan Dominik Kuhlmann; Pauline Wimberger; Konrad Grützmann; Natalie Herzog; Jan Heiner Küpper; Molly O'Reilly; S. Nashitha Kabir; Laura C. Sommerfeld; Kaomei Guan; Ben Wielockx; Larissa Fabritz; Stanley Nattel; Ursula Ravens; Dobromir Dobrev; Michael Wagner; Ali El-Armouche

doi:10.1161/CIRCRESAHA.121.319425

Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

Stephan R. Künzel, Maximilian Hoffmann, Silvio Weber, Karolina Künzel, Susanne Kämmerer, Mario Günscht, Erik Klapproth, Johanna S.E. Rausch, Mirna S. Sadek, Tomasz Kolanowski, Stefanie Meyer-Roxlau, Christopher Piorkowski, Sems M. Tugtekin, Stefan Rose-John, Xiaoke Yin, Manuel Mayr, Jan Dominik Kuhlmann, Pauline Wimberger, Konrad Grützmann, Natalie HerzogJan Heiner Küpper, Molly O'Reilly, S. Nashitha Kabir, Laura C. Sommerfeld, Kaomei Guan, Ben Wielockx, Larissa Fabritz, Stanley Nattel, Ursula Ravens, Dobromir Dobrev, Michael Wagner^*, Ali El-Armouche

^*Corresponding author for this work

Vascular Biology

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.

Original language	English
Pages (from-to)	804-820
Number of pages	17
Journal	Circulation Research
DOIs	https://doi.org/10.1161/CIRCRESAHA.121.319425
Publication status	Accepted/In press - 2021

Keywords

atrial fibrillation
fibroblasts
fibrosis
mesalamine
osteopontin

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10.1161/CIRCRESAHA.121.319425

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Künzel, S. R., Hoffmann, M., Weber, S., Künzel, K., Kämmerer, S., Günscht, M., Klapproth, E., Rausch, J. S. E., Sadek, M. S., Kolanowski, T., Meyer-Roxlau, S., Piorkowski, C., Tugtekin, S. M., Rose-John, S., Yin, X., Mayr, M., Kuhlmann, J. D., Wimberger, P., Grützmann, K., ... El-Armouche, A. (Accepted/In press). Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation. Circulation Research, 804-820. https://doi.org/10.1161/CIRCRESAHA.121.319425

@article{a371f28054ef4eeb98004ac8b281cd7b,

title = "Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation",

abstract = "Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.",

keywords = "atrial fibrillation, fibroblasts, fibrosis, mesalamine, osteopontin",

author = "K{\"u}nzel, {Stephan R.} and Maximilian Hoffmann and Silvio Weber and Karolina K{\"u}nzel and Susanne K{\"a}mmerer and Mario G{\"u}nscht and Erik Klapproth and Rausch, {Johanna S.E.} and Sadek, {Mirna S.} and Tomasz Kolanowski and Stefanie Meyer-Roxlau and Christopher Piorkowski and Tugtekin, {Sems M.} and Stefan Rose-John and Xiaoke Yin and Manuel Mayr and Kuhlmann, {Jan Dominik} and Pauline Wimberger and Konrad Gr{\"u}tzmann and Natalie Herzog and K{\"u}pper, {Jan Heiner} and Molly O'Reilly and Kabir, {S. Nashitha} and Sommerfeld, {Laura C.} and Kaomei Guan and Ben Wielockx and Larissa Fabritz and Stanley Nattel and Ursula Ravens and Dobromir Dobrev and Michael Wagner and Ali El-Armouche",

note = "Funding Information: This work was supported by grants from the DFG (German Research Foundation) within the CRC/Transregio 205/2 to B. Wielockx and A. El-Armouche (A02), DFG grant EL 270/7-3 to A. El-Armouche, the DFG IRTG 2251 to A. El-Armouche and S. K{\"a}mmerer. (D11) and DFG grant WA 2586/4-1 to M. Wagner. This work was supported by a “MeDDrive Start” grant of the Faculty of Medicine Carl Gustav Carus, Dresden (to S.R. K{\"u}nzel). The Institute of Cardiovascular Research, University of Birmingham, has received an Accelerator Award by the British Heart Foundation AA/18/2/34218. D. Dobrev and L. Fabritz received an EU Horizon 2020 MAESTRIA grant (965286). Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.",

year = "2021",

doi = "10.1161/CIRCRESAHA.121.319425",

language = "English",

pages = "804--820",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

}

Künzel, SR, Hoffmann, M, Weber, S, Künzel, K, Kämmerer, S, Günscht, M, Klapproth, E, Rausch, JSE, Sadek, MS, Kolanowski, T, Meyer-Roxlau, S, Piorkowski, C, Tugtekin, SM, Rose-John, S, Yin, X , Mayr, M, Kuhlmann, JD, Wimberger, P, Grützmann, K, Herzog, N, Küpper, JH, O'Reilly, M, Kabir, SN, Sommerfeld, LC, Guan, K, Wielockx, B, Fabritz, L, Nattel, S, Ravens, U, Dobrev, D, Wagner, M & El-Armouche, A 2021, 'Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation', Circulation Research, pp. 804-820. https://doi.org/10.1161/CIRCRESAHA.121.319425

TY - JOUR

T1 - Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

AU - Künzel, Stephan R.

AU - Hoffmann, Maximilian

AU - Weber, Silvio

AU - Künzel, Karolina

AU - Kämmerer, Susanne

AU - Günscht, Mario

AU - Klapproth, Erik

AU - Rausch, Johanna S.E.

AU - Sadek, Mirna S.

AU - Kolanowski, Tomasz

AU - Meyer-Roxlau, Stefanie

AU - Piorkowski, Christopher

AU - Tugtekin, Sems M.

AU - Rose-John, Stefan

AU - Yin, Xiaoke

AU - Mayr, Manuel

AU - Kuhlmann, Jan Dominik

AU - Wimberger, Pauline

AU - Grützmann, Konrad

AU - Herzog, Natalie

AU - Küpper, Jan Heiner

AU - O'Reilly, Molly

AU - Kabir, S. Nashitha

AU - Sommerfeld, Laura C.

AU - Guan, Kaomei

AU - Wielockx, Ben

AU - Fabritz, Larissa

AU - Nattel, Stanley

AU - Ravens, Ursula

AU - Dobrev, Dobromir

AU - Wagner, Michael

AU - El-Armouche, Ali

N1 - Funding Information: This work was supported by grants from the DFG (German Research Foundation) within the CRC/Transregio 205/2 to B. Wielockx and A. El-Armouche (A02), DFG grant EL 270/7-3 to A. El-Armouche, the DFG IRTG 2251 to A. El-Armouche and S. Kämmerer. (D11) and DFG grant WA 2586/4-1 to M. Wagner. This work was supported by a “MeDDrive Start” grant of the Faculty of Medicine Carl Gustav Carus, Dresden (to S.R. Künzel). The Institute of Cardiovascular Research, University of Birmingham, has received an Accelerator Award by the British Heart Foundation AA/18/2/34218. D. Dobrev and L. Fabritz received an EU Horizon 2020 MAESTRIA grant (965286). Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.

PY - 2021

Y1 - 2021

N2 - Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.

AB - Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.

KW - atrial fibrillation

KW - fibroblasts

KW - fibrosis

KW - mesalamine

KW - osteopontin

UR - http://www.scopus.com/inward/record.url?scp=85116844615&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.121.319425

DO - 10.1161/CIRCRESAHA.121.319425

M3 - Article

C2 - 34433292

AN - SCOPUS:85116844615

SN - 0009-7330

SP - 804

EP - 820

JO - Circulation Research

JF - Circulation Research

ER -

Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

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Keywords

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