Marcus A Ulleryd1, Filip Mjörnstedt1, Dimitra Panagaki1, Li Jin Yang1, Kajsa Engevall1, Saray Gutiérrez1, Yixin Wang2, Li-Ming Gan3, Holger Nilsson1, Erik Michaëlsson4, Maria E Johansson5. 1. Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 2. Crown Bioscience Inc., Shanghai, China. 3. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden. 4. Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden. 5. Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: maria.e.johansson@neuro.gu.se.
Abstract
BACKGROUND AND AIMS: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects. METHODS: AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro. RESULTS: α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983 decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages. CONCLUSIONS: This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/-mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans.
BACKGROUND AND AIMS: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects. METHODS:AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro. RESULTS: α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages. CONCLUSIONS: This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/-mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans.
Authors: Gunnar Engström; Viktor Hamrefors; Artur Fedorowski; Anders Persson; Maria E Johansson; Ellen Ostenfeld; Isabel Goncalves; Hanna Markstad; Linda S B Johnson; Margaretha Persson; Jonas Carlson; Pyotr G Platonov Journal: J Am Heart Assoc Date: 2022-03-30 Impact factor: 6.106
Authors: Maria E Hammarlund; C Joakim Ek; Sukaina Akar; Alma Karlsson; Bagmi Pattanaik; Filip Mjörnstedt; Pernilla Svedin; Maryam Ardalan; Eridan Rocha-Ferreira; Carina Mallard; Maria E Johansson Journal: Biomedicines Date: 2022-08-19
Authors: Maria E Hammarlund; Vladimer Darsalia; Filip Mjörnstedt; Bagmi Pattanaik; Carina Mallard; Eridan Rocha-Ferreira; Cesare Patrone; Maria E Johansson Journal: Biosci Rep Date: 2021-06-25 Impact factor: 3.840