Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

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

PY - 2021/10

Y1 - 2021/10

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 - Aged

KW - Animals

KW - Atrial Fibrillation/drug therapy

KW - Cells, Cultured

KW - Female

KW - Fibrosis

KW - Humans

KW - Male

KW - Mesalamine/pharmacology

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors

KW - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors

KW - Myocardium/metabolism

KW - Myofibroblasts/drug effects

KW - Osteopontin/metabolism

KW - Protein Kinase Inhibitors/pharmacology

KW - Protein Serine-Threonine Kinases/genetics

U2 - 10.1161/CIRCRESAHA.121.319425

DO - 10.1161/CIRCRESAHA.121.319425

M3 - SCORING: Journal article

C2 - 34433292

VL - 129

SP - 804

EP - 820

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 8

ER -