Beta arrestin 1 is a key regulator of pulmonary vascular tone
Abstract
Pulmonary arterial hypertension (PAH) is a serious disorder, in which increased vascular tone is one of the critical hallmarks. Since beta arrestins (bArrs) have been shown to regulate smooth muscle tone in the airways, we investigated the function of bArr1 in the pulmonary vasculature. Here, we report that bArr1 is essential for maintaining normal pulmonary arterial tone. Specifically, pulmonary arteries from bArr1−/− mice exhibited reduced NO-dependent vasorelaxation due to impaired soluble guanylyl cyclase (sGC) activity, which was restored by the heme-independent sGC activator BAY58-2667. We identified bArr1 as a binding partner of sGC and the sGC heme reductase cytochrome b5 reductase (Cyb5r3), indicating that bArr1 is vital for sensitizing sGC to NO. Finally, mice with either ubiquitous or smooth muscle-specific bArr1 deficiency developed pulmonary hypertension (PH). These findings highlight the important role of bArr1 in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Leonard F. Lebender
Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn
Alexander Seidinger
Department of Systems Physiology, Medical Faculty, Institute of Physiology, Ruhr University Bochum
Michaela Matthey
Department of Systems Physiology, Medical Faculty, Institute of Physiology, Ruhr University Bochum
Birte Dyck
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Knappschaft Kliniken University Hospital Bochum, Ruhr University Bochum
Christian Schlamm
Agnes Wittenborg Institute for Translational Cardiovascular Research, Herz- und Diabeteszentrum North Rhine-Westphalia, University Hospital of the Ruhr University Bochum
Abdullah Kaddoura
Department of Systems Physiology, Medical Faculty, Institute of Physiology, Ruhr University Bochum
Maximilian Hausherr
Medical Proteome Analysis, Center for Protein Diagnostics, Ruhr University Bochum
Britta Eggers
Medical Proteome Analysis, Center for Protein Diagnostics, Ruhr University Bochum
Katrin Marcus
Medical Proteome Analysis, Center for Protein Diagnostics, Ruhr University Bochum
Evi Kostenis
Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Volkmar Gieselmann
Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn
Michael Adamzik
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Knappschaft Kliniken University Hospital Bochum, Ruhr University Bochum
Anna Klinke
Agnes Wittenborg Institute for Translational Cardiovascular Research, Herz- und Diabeteszentrum North Rhine-Westphalia, University Hospital of the Ruhr University Bochum
Björn Koos
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Knappschaft Kliniken University Hospital Bochum, Ruhr University Bochum
Bernd K. Fleischmann
Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn
Daniela Wenzel
Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn