title: BMP-7 Treatment Increases M2 Macrophage Differentiation and Reduces Inflammation and Plaque Formation in Apo E-/- Mice.
abstract: Inflammation plays a fundamental role in the inception and development of atherosclerosis (ATH). Mechanisms of inflammation include the infiltration of monocytes into the injured area and subsequent differentiation into either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. We have previously published data suggesting bone morphogenetic protein-7 (BMP-7) enhances M2 macrophage differentiation and anti-inflammatory cytokine secretion in vitro. In this regard, we hypothesized BMP-7 would inhibit plaque formation in an animal model of ATH through monocytic plasticity mediation. ATH was generated in male and female Apo E(-/-) mice via partial left carotid artery (PLCA) ligation and mice were divided into 3 groups: Sham, PLCA, and PLCA+BMP-7 (200 ug/kg; i.v.). Our data suggest that BMP-7 inhibits plaque formation and increases arterial systolic velocity. Furthermore, we report inhibition of monocyte infiltration and a decrease in associated pro-inflammatory cytokines (MCP-1, TNF-α, and IL-6) in the PLCA+BMP-7 mice. In contrast, our data suggest a significant (p<0.05) increase in M2 macrophage populations with consequential enhanced anti-inflammatory cytokine (IL-1RA, IL-10, and Arginase 1) expression following BMP-7 treatment. We have also observed that mechanisms promoting monocyte into M2 macrophage differentiation by BMP-7 involve the upregulation and activation of the BMP-7 receptor (BMP-7RII). In conclusion, we report that BMP-7 has the potential to mediate cellular plasticity and mitigate the inflammatory immune response, which results in decreased plaque formation and improved blood velocity.
authors.affiliation: Division of Metabolic and Cardiovascular Sciences, Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States of America.
authors.forename: Dinender K
authors.initials: DK
authors.lastname: Singla
authors.affiliation: Division of Metabolic and Cardiovascular Sciences, Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States of America.
authors.forename: Reetu
authors.initials: R
authors.lastname: Singla
authors.affiliation: Division of Metabolic and Cardiovascular Sciences, Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001783:Blood Flow Velocity / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D055419:Bone Morphogenetic Protein 7; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052006:Bone Morphogenetic Protein Receptors, Type II; C544448:Arg1 protein, mouse; D001119:Arginase
references.citation: Cell Tissue Res. 2011 May;344(2):321-32
references.pmid: 21484415
references.citation: Biochem Biophys Res Commun. 2012 Jan 13;417(2):869-73
references.pmid: 22209843
references.citation: Immunol Res. 2013 Dec;57(1-3):86-98
references.pmid: 24203436
references.citation: Lipids Health Dis. 2011;10:211
references.pmid: 22082357
references.citation: J Immunol. 2003 Mar 1;170(5):2557-63
references.pmid: 12594282
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S178-82
references.pmid: 19060252
references.citation: Chem Res Toxicol. 2009 Aug;22(8):1376-85
references.pmid: 19645497
references.citation: J Cell Physiol. 2013 Jul;228(7):1577-83
references.pmid: 23335265
references.citation: Biomaterials. 2012 May;33(15):3792-802
references.pmid: 22386919
references.citation: Cytokine Growth Factor Rev. 2011 Aug;22(4):221-9
references.pmid: 21924665
references.citation: Arterioscler Thromb. 1994 Jan;14(1):141-7
references.pmid: 8274470
references.citation: Can J Physiol Pharmacol. 2012 Jul;90(7):947-51
references.pmid: 22720873
references.citation: Arterioscler Thromb Vasc Biol. 2003 Dec;23(12):2185-91
references.pmid: 14576075
references.citation: J Am Soc Nephrol. 2005 Jan;16(1):79-89
references.pmid: 15574511
references.citation: Am J Physiol Heart Circ Physiol. 2014 Sep 1;307(5):H762-72
references.pmid: 24993041
references.citation: J Cell Physiol. 2000 Jul;184(1):37-45
references.pmid: 10825232
references.citation: Acta Diabetol. 2013 Dec;50(6):977-82
references.pmid: 24085683
references.citation: PLoS One. 2009;4(12):e8198
references.pmid: 20011660
references.citation: Am J Pathol. 2002 Jun;160(6):2145-55
references.pmid: 12057918
references.citation: Cytokine. 2008 Aug;43(2):181-6
references.pmid: 18579408
references.citation: Mol Cell Biochem. 2013 Jan;372(1-2):267-73
references.pmid: 23054191
references.citation: Trends Immunol. 2004 Dec;25(12):677-86
references.pmid: 15530839
references.citation: Blood. 2010 Oct 14;116(15):e66-73
references.pmid: 20551377
references.citation: PLoS One. 2013;8(12):e84009
references.pmid: 24376781
references.citation: Cell. 2011 Apr 29;145(3):341-55
references.pmid: 21529710
references.citation: Cardiovasc Res. 2014 Mar 1;101(3):434-43
references.pmid: 24272771
references.citation: Lab Invest. 2005 Apr;85(4):474-86
references.pmid: 15696184
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: J Surg Res. 2012 Sep;177(1):e35-43
references.pmid: 22572621
references.citation: Cardiol Rev. 2014 May-Jun;22(3):147-51
references.pmid: 24618929
references.citation: Am J Physiol Heart Circ Physiol. 2014 Jan 1;306(1):H109-20
references.pmid: 24163071
references.citation: Circ Res. 2014 Jun 6;114(12):1852-66
references.pmid: 24902970
references.citation: J Cell Physiol. 2003 Aug;196(2):258-64
references.pmid: 12811818
references.citation: Circulation. 2006 Jun 13;113(23):2744-53
references.pmid: 16754802
references.citation: Front Immunol. 2014 Oct 17;5:514
references.pmid: 25368618