title: Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner.
abstract: Lithium at serum concentrations up to 1 mmol/L has been used in patients suffering from bipolar disorder for decades and has recently been shown to reduce the risk for ischemic stroke in these patients. The risk for stroke and thromboembolism depend not only on cerebral but also on general endothelial function and health; the entire endothelium as an organ is therefore pathophysiologically relevant. Regardless, the knowledge about the direct impact of lithium on endothelial function remains poor. We conducted an experimental study using lithium as pharmacologic pretreatment for murine, porcine and human vascular endothelium. We predominantly investigated endothelial vasorelaxation capacities in addition to human basal and dynamic (thrombin-/PAR-1 receptor agonist-impaired) barrier functioning including myosin light chain (MLC) phosphorylation (MLC-P). Low-dose therapeutic lithium concentrations (0.4 mmol/L) significantly augment the cholinergic endothelium-dependent vasorelaxation capacities of cerebral and thoracic arteries, independently of central and autonomic nerve system influences. Similar concentrations of lithium (0.2-0.4 mmol/L) significantly stabilized the dynamic thrombin-induced and PAR-1 receptor agonist-induced permeability of human endothelium, while even the basal permeability appeared to be stabilized. The lithium-attenuated dynamic permeability was mediated by a reduced endothelial MLC-P known to be followed by a lessening of endothelial cell contraction and paracellular gap formation. The well-known lithium-associated inhibition of inositol monophosphatase/glycogen synthase kinase-3-β signaling-pathways involving intracellular calcium concentrations in neurons seems to similarly occur in endothelial cells, too, but with different down-stream effects such as MLC-P reduction. This is the first study discovering low-dose lithium as a drug directly stabilizing human endothelium and ubiquitously augmenting cholinergic endothelium-mediated vasorelaxation. Our findings have translational and potentially clinical impact on cardiovascular and cerebrovascular disease associated with inflammation explaining why lithium can reduce, e.g., the risk for stroke. However, further clinical studies are warranted.
authors.affiliation: Division of Neurosurgery, St. Michael's Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Surgery, University of TorontoToronto, ON, Canada; Department of Neurology, University Hospital of Essen, University of Duisburg-EssenEssen, Germany.
authors.forename: Bert
authors.initials: B
authors.lastname: Bosche
authors.affiliation: Institute of Neurophysiology, Medical Faculty, University of CologneCologne, Germany; Department of Neurosurgery, Research Unit for Experimental Neurotraumatology, Medical University GrazGraz, Austria.
authors.forename: Marek
authors.initials: M
authors.lastname: Molcanyi
authors.affiliation: Division of Geriatric Psychiatry, Department of Psychiatry, Sunny Brook Health Sciences Centre, University of TorontoToronto, ON, Canada; Geri-PARTy Research Group, Department of Psychiatry, Jewish General Hospital, McGill UniversityMontréal, QC, Canada.
authors.forename: Soham
authors.initials: S
authors.lastname: Rej
authors.affiliation: Department of Neurology, University Hospital of Essen, University of Duisburg-EssenEssen, Germany; Department of Neurology, University of Göttingen Medical SchoolGöttingen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neurology, University Hospital of Essen, University of Duisburg-EssenEssen, Germany; Center for Neurology, Asklepios Hospitals SchildautalSeesen, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Obermann
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthToronto, ON, Canada; Department of Psychiatry, University of TorontoToronto, ON, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Medical Faculty Carl Gustav Carus, Institute of Physiology, Technical University of Dresden Dresden, Germany.
authors.forename: Anupam
authors.initials: A
authors.lastname: Das
authors.affiliation: Institute of Neurophysiology, Medical Faculty, University of Cologne Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Division of Neurosurgery, St. Michael's Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Surgery, University of Toronto Toronto, ON, Canada.
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
authors.affiliation: Medical Faculty Carl Gustav Carus, Institute of Physiology, Technical University of Dresden Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Noll
authors.affiliation: Medical Faculty Carl Gustav Carus, Institute of Physiology, Technical University of Dresden Dresden, Germany.
authors.forename: Frauke V
authors.initials: FV
authors.lastname: Härtel
keywords: bipolar disorder; blood-brain barrier; endothelial barrier; endothelial function; lithium; myosin light chain; stroke; vessel relaxation