Annette E Neele1, Marion J J Gijbels2, Saskia van der Velden3, Marten A Hoeksema3, Marieke C S Boshuizen3, Koen H M Prange3, Hung-Jen Chen3, Jan Van den Bossche3, Cindy P P A van Roomen3, Annelie Shami3, Johannes H M Levels4, Jeffrey Kroon4, Tina Lucas5, Stefanie Dimmeler5, Esther Lutgens6, Menno P J de Winther7. 1. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. Electronic address: a.e.neele@amc.uva.nl. 2. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands; Department of Pathology and Department of Molecular Genetics, CARIM, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands. 3. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. 4. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. 5. Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Mein, Germany. 6. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Pettenkoferstrasse 9, 80336, Munich, Germany. 7. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Pettenkoferstrasse 9, 80336, Munich, Germany. Electronic address: m.dewinther@amc.uva.nl.
Abstract
BACKGROUND AND AIMS: Atherosclerosis is a lipid-driven chronic inflammatory disorder of the arteries, and monocytes and macrophages play a central role in this process. Within the atherosclerotic lesion, macrophages can scavenge modified lipids and become the so-called foam cells. We previously reported that the epigenetic enzyme Kdm6b (also known as Jmjd3) controls the pro-fibrotic transcriptional profile of peritoneal foam cells. Given the importance of these cells in atherosclerosis, we now studied the effect of myeloid Kdm6b on disease progression. METHODS: Bone marrow of myeloid Kdm6b deficient (Kdm6bdel) mice or wild type littermates (Kdm6bwt) was transplanted to lethally irradiated Ldlr-/- mice fed a high fat diet for 9 weeks to induce atherosclerosis. RESULTS: Lesion size was similar in Kdm6bwt and Kdm6bdel transplanted mice. However, lesions of Kdm6bdel mice contained more collagen and were more necrotic. Pathway analysis on peritoneal foam cells showed that the pathway involved in leukocyte chemotaxis was most significantly upregulated. Although macrophage and neutrophil content was similar after 9 weeks of high fat diet feeding, the relative increase in collagen content and necrosis revealed that atherosclerotic lesions in Kdm6bdel mice progress faster. CONCLUSION: Myeloid Kdm6b deficiency results in more advanced atherosclerosis.
BACKGROUND AND AIMS: Atherosclerosis is a lipid-driven chronic inflammatory disorder of the arteries, and monocytes and macrophages play a central role in this process. Within the atherosclerotic lesion, macrophages can scavenge modified lipids and become the so-called foam cells. We previously reported that the epigenetic enzyme Kdm6b (also known as Jmjd3) controls the pro-fibrotic transcriptional profile of peritoneal foam cells. Given the importance of these cells in atherosclerosis, we now studied the effect of myeloid Kdm6b on disease progression. METHODS: Bone marrow of myeloid Kdm6b deficient (Kdm6bdel) mice or wild type littermates (Kdm6bwt) was transplanted to lethally irradiated Ldlr-/- mice fed a high fat diet for 9 weeks to induce atherosclerosis. RESULTS: Lesion size was similar in Kdm6bwt and Kdm6bdel transplanted mice. However, lesions of Kdm6bdel mice contained more collagen and were more necrotic. Pathway analysis on peritoneal foam cells showed that the pathway involved in leukocyte chemotaxis was most significantly upregulated. Although macrophage and neutrophil content was similar after 9 weeks of high fat diet feeding, the relative increase in collagen content and necrosis revealed that atherosclerotic lesions in Kdm6bdel mice progress faster. CONCLUSION:Myeloid Kdm6b deficiency results in more advanced atherosclerosis.
Authors: Tatyana Kuznetsova; Koen H M Prange; Christopher K Glass; Menno P J de Winther Journal: Nat Rev Cardiol Date: 2019-10-02 Impact factor: 32.419
Authors: Frank M Davis; Lam C Tsoi; William J Melvin; Aaron denDekker; Rachael Wasikowski; Amrita D Joshi; Sonya Wolf; Andrea T Obi; Allison C Billi; Xianying Xing; Christopher Audu; Bethany B Moore; Steven L Kunkel; Alan Daugherty; Hong S Lu; Johann E Gudjonsson; Katherine A Gallagher Journal: J Exp Med Date: 2021-06-07 Impact factor: 14.307
Authors: Annette E Neele; Hung-Jen Chen; Marion J J Gijbels; Saskia van der Velden; Marten A Hoeksema; Marieke C S Boshuizen; Jan Van den Bossche; Anton T Tool; Hanke L Matlung; Timo K van den Berg; Esther Lutgens; Menno P J de Winther Journal: Front Immunol Date: 2021-01-26 Impact factor: 7.561
Authors: Cassidy M R Blackburn; Robert M Schilke; Aimee E Vozenilek; Sunitha Chandran; Temitayo T Bamgbose; Brian N Finck; Matthew D Woolard Journal: Atherosclerosis Date: 2021-07-01 Impact factor: 6.847
Authors: Annette E Neele; Lisa Willemsen; Hung-Jen Chen; Kim E Dzobo; Menno P J de Winther Journal: Curr Opin Lipidol Date: 2020-12 Impact factor: 4.616