The Role of NOX2-Derived Reactive Oxygen Species in the Induction of Endothelin-Converting Enzyme-1 by Angiotensin II
Michael Adu-Gyamfi,
Claudia Goettsch,
Julian Kamhieh-Milz,
Lei Chen,
Anna Maria Pfefferkorn,
Anja Hofmann,
Coy Brunssen,
Gregor Müller,
Thomas Walther,
Muhammad Imtiaz Ashraf,
Henning Morawietz,
Janusz Witowski,
Rusan Catar
Affiliations
Michael Adu-Gyamfi
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Claudia Goettsch
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Julian Kamhieh-Milz
Institute of Transfusion Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Lei Chen
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Anna Maria Pfefferkorn
Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Anja Hofmann
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Coy Brunssen
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Gregor Müller
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Thomas Walther
Medical School Berlin (MSB), 14197 Berlin, Germany
Muhammad Imtiaz Ashraf
Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Henning Morawietz
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Janusz Witowski
Department of Pathophysiology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
Rusan Catar
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
Endothelin-1 is a key regulator of vascular tone and blood pressure in health and disease. We have recently found that ET-1 production in human microvascular endothelial cells (HMECs) can be promoted by angiotensin II (Ang II) through a novel mechanism involving octamer-binding transcription factor-1 (Oct-1), NADPH oxidase-2 (NOX2), and superoxide anions. As the formation of bioactive ET-1 also depends on endothelin-converting enzyme-1 (ECE-1), we investigated the transcriptional regulation of the ECE1 gene. We found that exposure of HMECs to Ang II resulted in a concentration- and time-dependent increase in ECE1 mRNA expression. Pharmacological inhibition of ECE-1 reduced Ang II-stimulated ET-1 release to baseline values. The effect of Ang II on ECE1 mRNA expression was associated with Oct-1 binding to the ECE1 promoter, resulting in its increased activity. Consequently, the Ang II-stimulated increase in ECE1 mRNA expression could be prevented by siRNA-mediated Oct-1 inhibition. It could also be abolished by silencing the NOX2 gene and neutralizing superoxide anions with superoxide dismutase. In mice fed a high-fat diet, cardiac expression of Ece1 mRNA increased in wild-type mice but not in Nox2-deficient animals. It can be concluded that Ang II engages Oct-1, NOX2, and superoxide anions to stimulate ECE1 expression in the endothelium.
