TY - GEN A1 - Künzel, Stephan R. A1 - Rausch, Johanna S. E. A1 - Schäffer, Charlotte A1 - Hoffmann, Maximilian A1 - Künzel, Karolina A1 - Klapproth, Erik A1 - Kant, Theresa A1 - Herzog, Natalie A1 - Küpper, Jan-Heiner A1 - Lorenz, Kristina A1 - Dudek, Svenja A1 - Emig, Ramona A1 - Ravens, Ursula A1 - Rog‐Zielinska, Eva A. A1 - Peyronnet, Rémi A1 - El-Armouche, Ali T1 - Modeling atrial fibrosis in vitro - Generation and characterization of a novel human atrial fibroblast cell line T2 - FEBS Open Bio N2 - Atrial fibrillation (AF) is regularly accompanied by cardiac fibrosis and concomitant heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge about the underlying mechanisms is limited, which prevents effective pharmacotherapy. A deeper understanding of cardiac fibroblasts is essential to meet this need. We previously described phenotypic and functional differences between atrial fibroblasts from patients in sinus rhythm and with AF. Herein, we established and characterized a novel human atrial fibroblast line, which displays typical fibroblast morphology and function comparable to primary cells but with improved proliferation capacity and low spontaneous myofibroblast differentiation. These traits make our model suitable for the study of fibrosis mechanisms and for drug screening aimed at developing effective antifibrotic pharmacotherapy. KW - cardiovascular disease KW - cell culture KW - cell lines KW - fibroblasts KW - fibrosis KW - heart Y1 - 2020 U6 - https://doi.org/10.1002/2211-5463.12896 SN - 2211-5463 VL - 10 IS - 7 SP - 1210 EP - 1218 ER - TY - GEN A1 - Künzel, Stephan R. A1 - Hoffmann, Maximilian A1 - Weber, Silvio A1 - Künzel, Karolina A1 - Kämmerer, Susanne A1 - Günscht, Mario A1 - Klapproth, Erik A1 - Rausch, Johanna S. E. A1 - Sadek, Mirna S. A1 - Kolanowski, Tomasz A1 - Meyer-Roxlau, Stefanie A1 - Piorkowski, Christopher A1 - Tugtekin, Sems M. A1 - Rose-John, Stefan A1 - Yin, Xiaoke A1 - Mayr, Manuel A1 - Kuhlmann, Jan Dominik A1 - Wimberger, Pauline A1 - Grützmann, Konrad A1 - Herzog, Natalie A1 - Küpper, Jan-Heiner A1 - O’Reilly, Molly A1 - Kabir, S. Nashitha A1 - Sommerfeld, Laura C. A1 - Guan, Kaomei A1 - Wielockx, Ben A1 - Fabritz, Larissa A1 - Nattel, Stanley A1 - Ravens, Ursula A1 - Dobrev, Dobromir A1 - Wagner, Michael A1 - El-Armouche, Ali T1 - Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation T2 - Circulation Research 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. KW - atrial fibrillation KW - fibroblasts KW - fibrosis KW - mesalamine KW - osteopontin Y1 - 2021 UR - https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.121.319425 U6 - https://doi.org/10.1161/CIRCRESAHA.121.319425 SN - 1524-4571 SN - 0009-7330 VL - 129 IS - 8 SP - 804 EP - 820 ER - TY - GEN A1 - Kronstein-Wiedemann, Romy A1 - Teichert, Madeleine A1 - Michel, Elisa A1 - Berg, Janina A1 - Robinson, George A1 - Tausche, Kristin A1 - Kolditz, Martin A1 - Bergleiter, Johannes A1 - Thiel, Jessica A1 - Koschel, Dirk A1 - Künzel, Stephan R. A1 - Hölig, Kristina A1 - Tonn, Torsten A1 - Rossol, Manuela T1 - Dysregulated monocyte compartment in PACS patients T2 - Frontiers in immunology N2 - Introduction 1-5% of all patients with COVID-19, a disease caused by infection with Severe Acute Respiratory Syndrome Virus 2 (SARS-Cov-2), even those with mild COVID-19 symptoms, continue to have symptoms after initial recovery. Symptoms associated with the post-acute sequelae of COVID-19 (PACS) include, among others, fatigue, shortness of breath, cough, and cognitive dysfunction. Since the dysregulated immune response appears to be caused by the sustained activation of certain immune cells, including monocytes, and the release of specific cytokines, the aim of our study was to investigate the effect of PACS disease on monocyte subpopulations. Methods Twenty-two healthy and thirty-two patients with PACS were included into this study. We performed blood gas analysis and measured hematological parameters from peripheral blood of PACS patients and compared them with healthy donors. Surface markers to identify monocyte subpopulations were analyzed by flow cytometry. Results PACS patients had higher numbers of intermediate and CD56+ monocytes, whereas the numbers of total monocytes, classical and non-classical monocytes were normal compared to healthy donors. Comparison of patients with and without fatigue, cough, and dyspnea showed no difference in monocyte subset frequencies. However, patients with cognitive dysfunction had increased numbers of non-classical monocytes compared to patients without this symptom. Discussion This suggests a disturbed homeostasis of the monocyte subsets in the peripheral blood of patients with PACS. KW - Monocytes KW - Intermediate monocytes KW - CD56+ monocytes KW - COVID-19 KW - PACS KW - SARS-CoV-2 Y1 - 2025 U6 - https://doi.org/10.3389/fimmu.2025.1613034 SN - 1664-3224 VL - 16 SP - 1 EP - 11 PB - Frontiers Media S.A. CY - Lausanne ER -