Sonja Kleeschulte1, Johann Jerrentrup2, Daniel Gorski2, Joachim Schmitt2, Anke C Fender3. 1. Klinik für Gastroenterologie, Hepatologie und Infektiologie, Klinikum der Heinrich-Heine-Universität, 20225 Düsseldorf, Germany(1). 2. Institut für Pharmakologie & Klinische Pharmakologie, Klinikum der Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany. 3. Experimentelle und Klinische Hämostaseologie, Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie, Universitätsklinikum Münster, 48149 Münster, Germany. Electronic address: afender@uni-muenster.de.
Abstract
BACKGROUND: Thrombin promotes cardiac fibroblast proliferation and fibrosis via protease-activated receptor (PAR-1). PAR-4 is reportedly absent in cardiac fibroblasts. In smooth muscle cells, PAR-4 expression is also low but increases upon hyperglycemia and contributes to vascular remodelling in diabetic mice. We examined if PAR-4 is a glucose-responsive gene with remodelling-related functions in cardiac fibroblasts. METHODS AND RESULTS: Cardiac PAR-4 increased in mice with streptozotocin- or diabetogenic diet (DD)-induced diabetes. PAR-4 mRNA and protein were detectable in cardiac fibroblasts from chow-fed mice and increased in high (HG, 25mM) vs. low glucose (LG; 5.5mM) cultures. Conversely PAR-4 mRNA was higher in fibroblasts from DD-fed mice but reduced in LG cultures. Cardiac fibroblasts in HG culture responded more strongly to thrombin or PAR-4 activating peptide in terms of migration (wound-scratch assay), remodelling-associated gene expression (interleukin 6, alpha smooth muscle actin) and oxidative stress (dihydroethidium fluorescence). CONCLUSION: PAR-4 is expressed in mouse cardiac fibroblasts and is dynamically regulated by extracellular glucose in vitro and diabetes in vivo, thereby impacting on fibroblast functions relevant for cardiac remodelling. These findings add further evidence for the usefulness of the recently developed PAR-4 antagonists in clinical settings.
BACKGROUND:Thrombin promotes cardiac fibroblast proliferation and fibrosis via protease-activated receptor (PAR-1). PAR-4 is reportedly absent in cardiac fibroblasts. In smooth muscle cells, PAR-4 expression is also low but increases upon hyperglycemia and contributes to vascular remodelling in diabeticmice. We examined if PAR-4 is a glucose-responsive gene with remodelling-related functions in cardiac fibroblasts. METHODS AND RESULTS: Cardiac PAR-4 increased in mice with streptozotocin- or diabetogenic diet (DD)-induced diabetes. PAR-4 mRNA and protein were detectable in cardiac fibroblasts from chow-fed mice and increased in high (HG, 25mM) vs. low glucose (LG; 5.5mM) cultures. Conversely PAR-4 mRNA was higher in fibroblasts from DD-fed mice but reduced in LG cultures. Cardiac fibroblasts in HG culture responded more strongly to thrombin or PAR-4 activating peptide in terms of migration (wound-scratch assay), remodelling-associated gene expression (interleukin 6, alpha smooth muscle actin) and oxidative stress (dihydroethidium fluorescence). CONCLUSION:PAR-4 is expressed in mouse cardiac fibroblasts and is dynamically regulated by extracellular glucose in vitro and diabetes in vivo, thereby impacting on fibroblast functions relevant for cardiac remodelling. These findings add further evidence for the usefulness of the recently developed PAR-4 antagonists in clinical settings.
Authors: Anke C Fender; Sonja Kleeschulte; Svenja Stolte; Katja Leineweber; Markus Kamler; Johannes Bode; Na Li; Dobromir Dobrev Journal: Basic Res Cardiol Date: 2020-01-07 Impact factor: 17.165
Authors: Daniel J Gorski; Anne Petz; Christina Reichert; Sören Twarock; Maria Grandoch; Jens W Fischer Journal: Sci Rep Date: 2019-02-12 Impact factor: 4.379
Authors: Juan E Camacho Londoño; André Marx; Axel E Kraft; Alexander Schürger; Christin Richter; Alexander Dietrich; Peter Lipp; Lutz Birnbaumer; Marc Freichel Journal: Cells Date: 2020-01-29 Impact factor: 6.600