@misc{SteinbrechtKoenigSchmidtkeetal., author = {Steinbrecht, Susanne and K{\"o}nig, Rosalie and Schmidtke, Kai-Uwe and Herzog, Natalie and Scheibner, Katrin and Kr{\"u}ger-Genge, Anne and Jung, Friedrich and Kammerer, Sarah and K{\"u}pper, Jan-Heiner}, title = {Metabolic activity testing can underestimate acute drug cytotoxicity as revealed by HepG2 cell clones overexpressing cytochrome P450 2C19 and 3A4}, series = {Toxicology}, volume = {412}, journal = {Toxicology}, issn = {0300-483X}, doi = {10.1016/j.tox.2018.11.008}, pages = {37 -- 47}, language = {en} } @misc{SteinbrechtPfeiferHerzogetal., author = {Steinbrecht, Susanne and Pfeifer, Nadine and Herzog, Natalie and Katzenberger, Nadine and Schulz, Christian and Kammerer, Sarah and K{\"u}pper, Jan-Heiner}, title = {HepG2-1A2 C2 and C7: Lentivirus vector-mediated stable and functional overexpression of cytochrome P450 1A2 in human hepatoblastoma cells}, series = {Toxicology Letters}, volume = {319}, journal = {Toxicology Letters}, issn = {0378-4274}, doi = {10.1016/j.toxlet.2019.11.006}, pages = {155 -- 159}, abstract = {Novel HepG2 cell clones 1A2 C2 and 1A2 C7 were independently generated by lentiviral transduction to functionally overexpress cytochrome P450 1A2 (CYP1A2). We found similar and stable CYP1A2 transcript and protein levels in both cell clones leading to specific enzyme activities of about 370 pmol paracetamol x min-1 x mg-1 protein analyzed by phenacetin conversion. Both clones showed dramatically increased sensitivity to the hepatotoxic compound aflatoxin B1 (EC50<100 nM) when compared to parental HepG2 cells (EC50 ∼5 μM). Thus, newly established cell lines are an appropriate tool to study metabolism and toxicity of substances depending on conversion by CYP1A2.}, language = {en} } @misc{KuenzelHoffmannWeberetal., author = {K{\"u}nzel, Stephan R. and Hoffmann, Maximilian and Weber, Silvio and K{\"u}nzel, Karolina and K{\"a}mmerer, Susanne and G{\"u}nscht, Mario and Klapproth, Erik and Rausch, Johanna S. E. and Sadek, Mirna S. and Kolanowski, Tomasz and Meyer-Roxlau, Stefanie and Piorkowski, Christopher and Tugtekin, Sems M. and Rose-John, Stefan and Yin, Xiaoke and Mayr, Manuel and Kuhlmann, Jan Dominik and Wimberger, Pauline and Gr{\"u}tzmann, Konrad and Herzog, Natalie and K{\"u}pper, Jan-Heiner and O'Reilly, Molly and Kabir, S. Nashitha and Sommerfeld, Laura C. and Guan, Kaomei and Wielockx, Ben and Fabritz, Larissa and Nattel, Stanley and Ravens, Ursula and Dobrev, Dobromir and Wagner, Michael and El-Armouche, Ali}, title = {Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation}, series = {Circulation Research}, volume = {129}, journal = {Circulation Research}, number = {8}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.121.319425}, pages = {804 -- 820}, 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.}, language = {en} }