title: Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice.
abstract: Macrophage inflammation marks all stages of atherogenesis, and AMPK is a regulator of macrophage inflammation. We therefore generated myeloid α1AMPK knockout (MAKO) mice on the LDL receptor knockout (LDLRKO) background to investigate whether myeloid deletion of α1AMPK exacerbates atherosclerosis. When fed an atherogenic diet, MAKO/LDLRKO mice displayed exacerbated atherosclerosis compared with LDLRKO mice. To determine the underlying pathophysiological pathways, we characterized macrophage inflammation/chemotaxis and lipid/cholesterol metabolism in MAKO/LDLRKO mice. Myeloid deletion of α1AMPK increased macrophage inflammatory gene expression and enhanced macrophage migration and adhesion to endothelial cells. Remarkably, MAKO/LDLRKO mice also displayed higher composition of circulating chemotaxically active Ly-6C(high) monocytes, enhanced atherosclerotic plaque chemokine expression, and monocyte recruitment into plaques, leading to increased atherosclerotic plaque macrophage content and inflammation. MAKO/LDLRKO mice also exhibited higher plasma LDL and VLDL cholesterol content, increased circulating apolipoprotein B (apoB) levels, and higher liver apoB expression. We conclude that macrophage α1AMPK deficiency promotes atherogenesis in LDLRKO mice and is associated with enhanced macrophage inflammation and hypercholesterolemia and that macrophage α1AMPK may serve as a therapeutic target for prevention and treatment of atherosclerosis.
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zha
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA hshi3@gsu.edu bxue@gsu.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, GA hshi3@gsu.edu bxue@gsu.edu.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency*; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000209:etiology*; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004036:Diet, Atherogenic / Q000009:adverse effects; D018450:Disease Progression; D006937:Hypercholesterolemia / Q000209:etiology; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology; D022423:Myeloid Cells / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D011973:Receptors, LDL; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases
references.citation: Nat Med. 2009 Dec;15(12):1383-91
references.pmid: 19966778
references.citation: Immunol Cell Biol. 2014 Apr;92(4):340-5
references.pmid: 24638063
references.citation: J Biol Chem. 2010 Oct 22;285(43):33499-509
references.pmid: 20713354
references.citation: J Am Coll Cardiol. 2009 Dec 1;54(23):2129-38
references.pmid: 19942084
references.citation: Cell Metab. 2010 Dec 1;12(6):580-92
references.pmid: 21109191
references.citation: J Immunol. 2015 Aug 15;195(4):1732-43
references.pmid: 26136425
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1287-98
references.pmid: 19342510
references.citation: J Endotoxin Res. 2006;12(3):181-92
references.pmid: 16719989
references.citation: J Clin Invest. 2007 Jan;117(1):185-94
references.pmid: 17200718
references.citation: J Exp Med. 2014 Jul 28;211(8):1525-31
references.pmid: 25024137
references.citation: Nature. 2010 Dec 2;468(7324):653-8
references.pmid: 21124450
references.citation: J Biol Chem. 2010 Jun 18;285(25):19051-9
references.pmid: 20421294
references.citation: Annu Rev Immunol. 2009;27:165-97
references.pmid: 19302038
references.citation: J Clin Invest. 2007 Jan;117(1):195-205
references.pmid: 17200719
references.citation: Endocrinology. 2011 Mar;152(3):836-46
references.pmid: 21239433
references.citation: Autophagy. 2015;11(2):271-84
references.pmid: 25650776
references.citation: Nature. 2000 Sep 14;407(6801):233-41
references.pmid: 11001066
references.citation: J Clin Invest. 1993 Aug;92(2):883-93
references.pmid: 8349823
references.citation: J Biol Chem. 2009 Dec 11;284(50):34561-9
references.pmid: 19843515
references.citation: J Clin Invest. 2006 Jun;116(6):1494-505
references.pmid: 16691291
references.citation: Curr Vasc Pharmacol. 2009 Apr;7(2):234-43
references.pmid: 19356007
references.citation: J Lipid Res. 1981 Feb;22(2):339-58
references.pmid: 6787159
references.citation: J Biol Chem. 2006 Sep 8;281(36):26602-14
references.pmid: 16809344
references.citation: J Lipid Res. 2015 Jun;56(6):1191-205
references.pmid: 25921305
references.citation: J Physiol. 2006 Jul 1;574(Pt 1):73-83
references.pmid: 16709629
references.citation: PLoS One. 2012;7(11):e49935
references.pmid: 23183898
references.citation: Nat Immunol. 2011 May;12 (5):408-15
references.pmid: 21478880
references.citation: PLoS Pathog. 2014 Sep 11;10(9):e1004372
references.pmid: 25211233
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: J Leukoc Biol. 2010 Jul;88(1):169-80
references.pmid: 20400676
references.citation: J Immunol. 2008 Dec 15;181(12):8633-41
references.pmid: 19050283
references.citation: Transgenic Res. 1999 Aug;8(4):265-77
references.pmid: 10621974
references.citation: Arterioscler Thromb Vasc Biol. 2005 May;25(5):904-14
references.pmid: 15731497
references.citation: J Clin Invest. 2006 Jan;116(1):115-24
references.pmid: 16341265
references.citation: Mol Cell. 1998 Aug;2(2):275-81
references.pmid: 9734366
references.citation: J Lipid Res. 2004 Jul;45(7):1169-96
references.pmid: 15102878
references.citation: Nature. 1998 Aug 27;394(6696):894-7
references.pmid: 9732872
references.citation: Circ Res. 2007 Mar 30;100(6):884-93
references.pmid: 17322176
references.citation: J Lipid Res. 1990 Mar;31(3):455-66
references.pmid: 2341808
references.citation: Circulation. 2008 Sep 30;118(14):1467-75
references.pmid: 18794388
references.citation: Endocrinology. 2014 Dec;155(12 ):4925-38
references.pmid: 25251587
references.citation: Nat Rev Cardiol. 2009 Jun;6(6):399-409
references.pmid: 19399028
references.citation: J Clin Invest. 2011 Dec;121(12):4903-15
references.pmid: 22080866
references.citation: Mol Cell Biol. 2010 Oct;30(19):4712-21
references.pmid: 20647536