Andreas Zietzer1, Eva Steffen1, Sven Niepmann1, Philip Düsing1, Mohammed Rabiul Hosen1, Weiyi Liu1, Paul Jamme1, Baravan Al-Kassou1, Philipp Roger Goody1, Sebastian Zimmer1, Katrin S Reiners2, Alexander Pfeifer3, Michael Böhm4, Nikos Werner1,5, Georg Nickenig1, Felix Jansen1. 1. Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. 2. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. 3. Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. 4. Medical Department III, Faculty of Medicine, Saarland University Medical Center, Saarland University, Kirrberger Straße 100, 66421 Homburg, Germany. 5. Medical Department II, Krankenhaus der Barmherzigen Brüder Trier, Nordallee 1, 54292 Trier, Germany.
Abstract
AIMS: Chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease (CAD). For both, CKD and CAD, the intercellular transfer of microRNAs (miRs) through extracellular vesicles (EVs) is an important factor of disease development. Whether the combination of CAD and CKD affects endothelial function through cellular crosstalk of EV-incorporated miRs is still unknown. METHODS AND RESULTS: Out of 172 screened CAD patients, 31 patients with CAD + CKD were identified and matched with 31 CAD patients without CKD. Additionally, 13 controls without CAD and CKD were included. Large EVs from CAD + CKD patients contained significantly lower levels of the vasculo-protective miR-130a-3p and miR-126-3p compared to CAD patients and controls. Flow cytometric analysis of plasma-derived EVs revealed significantly higher numbers of endothelial cell-derived EVs in CAD and CAD + CKD patients compared to controls. EVs from CAD + CKD patients impaired target human coronary artery endothelial cell (HCAEC) proliferation upon incubation in vitro. Consistent with the clinical data, treatment with the uraemia toxin indoxyl sulfate (IS)-reduced miR-130a-3p levels in HCAEC-derived EVs. EVs from IS-treated donor HCAECs-reduced proliferation and re-endothelialization in EV-recipient cells and induced an anti-angiogenic gene expression profile. In a mouse-experiment, intravenous treatment with EVs from IS-treated endothelial cells significantly impaired endothelial regeneration. On the molecular level, we found that IS leads to an up-regulation of the heterogenous nuclear ribonucleoprotein U (hnRNPU), which retains miR-130a-3p in the cell leading to reduced vesicular miR-130a-3p export and impaired EV-recipient cell proliferation. CONCLUSION: Our findings suggest that EV-miR-mediated vascular intercellular communication is altered in patients with CAD and CKD, promoting CKD-induced endothelial dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease (CAD). For both, CKD and CAD, the intercellular transfer of microRNAs (miRs) through extracellular vesicles (EVs) is an important factor of disease development. Whether the combination of CAD and CKD affects endothelial function through cellular crosstalk of EV-incorporated miRs is still unknown. METHODS AND RESULTS: Out of 172 screened CAD patients, 31 patients with CAD + CKD were identified and matched with 31 CAD patients without CKD. Additionally, 13 controls without CAD and CKD were included. Large EVs from CAD + CKD patients contained significantly lower levels of the vasculo-protective miR-130a-3p and miR-126-3p compared to CAD patients and controls. Flow cytometric analysis of plasma-derived EVs revealed significantly higher numbers of endothelial cell-derived EVs in CAD and CAD + CKD patients compared to controls. EVs from CAD + CKD patients impaired target human coronary artery endothelial cell (HCAEC) proliferation upon incubation in vitro. Consistent with the clinical data, treatment with the uraemia toxin indoxyl sulfate (IS)-reduced miR-130a-3p levels in HCAEC-derived EVs. EVs from IS-treated donor HCAECs-reduced proliferation and re-endothelialization in EV-recipient cells and induced an anti-angiogenic gene expression profile. In a mouse-experiment, intravenous treatment with EVs from IS-treated endothelial cells significantly impaired endothelial regeneration. On the molecular level, we found that IS leads to an up-regulation of the heterogenous nuclear ribonucleoprotein U (hnRNPU), which retains miR-130a-3p in the cell leading to reduced vesicular miR-130a-3p export and impaired EV-recipient cell proliferation. CONCLUSION: Our findings suggest that EV-miR-mediated vascular intercellular communication is altered in patients with CAD and CKD, promoting CKD-induced endothelial dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Philip Düsing; Andreas Zietzer; Philip Roger Goody; Mohammed Rabiul Hosen; Christian Kurts; Georg Nickenig; Felix Jansen Journal: J Mol Med (Berl) Date: 2021-01-22 Impact factor: 4.599
Authors: Ankita Garg; Benjamin Seeliger; Anselm A Derda; Sascha David; Christian Bär; Thomas Thum; Ke Xiao; Anika Gietz; Kristian Scherf; Kristina Sonnenschein; Isabell Pink; Marius M Hoeper; Tobias Welte; Johann Bauersachs Journal: Eur J Heart Fail Date: 2021-03-05 Impact factor: 17.349
Authors: Andreas Zietzer; Baravan Al-Kassou; Paul Jamme; Verena Rolfes; Eva Steffen; Marko Bulic; Mohammed Rabiul Hosen; Philip Roger Goody; Vedat Tiyerili; Sebastian Zimmer; Jan Wilko Schrickel; Alexander Sedaghat; Bernardo S Franklin; Nikos Werner; Georg Nickenig; Felix Jansen Journal: Clin Res Cardiol Date: 2021-06-01 Impact factor: 5.460
Authors: Andreas Zietzer; Alina Lisann Jahnel; Marko Bulic; Katharina Gutbrod; Philip Düsing; Mohammed Rabiul Hosen; Peter Dörmann; Nikos Werner; Georg Nickenig; Felix Jansen Journal: Cell Mol Life Sci Date: 2021-12-24 Impact factor: 9.261