title: Expanding role of delta-like 4 mediated notch signaling in cardiovascular and metabolic diseases.
abstract: Cardiometabolic disease, a global health threat, has been linked to chronic inflammation, in which activated macrophages play a key role. Macrophages are highly heterogeneous hematopoietic cells found in nearly every tissue in the body. Various stimuli recruit monocytes into the cardiovascular system and metabolic organs, where they differentiate to macrophages, and activate these pro-inflammatory phagocytes, leading to the initiation and development of inflammation in these organs. Key regulators of macrophage activation therefore may serve as therapeutic targets for cardiometabolic disease. The Notch signaling pathway, involving 5 ligands and 4 receptors, regulates the differentiation of various cell types during development, and also contributes to the disease processes in adults. We found that the Notch ligand delta-like 4 (Dll4) activates macrophages in vitro as determined by the induction of genes and pathways associated with cardiovascular and metabolic disorders. Our recent study demonstrated in vivo that blockade of Dll4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat; chronic atherosclerosis; arterial and valvular calcification; insulin resistance; and fatty liver. These results suggest that Dll4-mediated Notch signaling participates in the shared disease mechanisms for cardiovascular and metabolic disorders. This review summarizes the role of macrophages and Dll4/Notch signaling in the development of inflammation in both the cardiovascular system and metabolic organs.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D005234:Fatty Liver / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014652:Vascular Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch
references.citation: Cell. 2010 Mar 19;140(6):900-17
references.pmid: 20303879
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: Blood. 2009 Apr 9;113(15):3631-9
references.pmid: 19218547
references.citation: Lab Invest. 2008 Jan;88(1):11-7
references.pmid: 18059366
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):E1868-77
references.pmid: 22699504
references.citation: Circulation. 2007 Dec 11;116(24):2782-5
references.pmid: 18071088
references.citation: Int Immunol. 2008 Jun;20(6):763-73
references.pmid: 18381350
references.citation: Annu Rev Immunol. 2010;28:343-65
references.pmid: 20192807
references.citation: Nature. 2007 Jun 21;447(7147):972-8
references.pmid: 17538624
references.citation: Clin Genet. 2003 Dec;64(6):461-72
references.pmid: 14986825
references.citation: Nat Med. 2011 Jul 31;17(8):961-7
references.pmid: 21804540
references.citation: J Biomed Sci. 2011 Aug 15;18:56
references.pmid: 21843347
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Atherosclerosis. 2012 Dec;225(2):296-303
references.pmid: 23078884
references.citation: Nat Rev Cancer. 2007 May;7(5):327-31
references.pmid: 17457300
references.citation: Annu Rev Pathol. 2008;3:587-613
references.pmid: 18039126
references.citation: Circ Res. 2007 Jun 8;100(11):1556-68
references.pmid: 17556669
references.citation: J Clin Invest. 2007 Jan;117(1):89-93
references.pmid: 17200712
references.citation: Biochem Biophys Res Commun. 2012 Feb 24;418(4):799-805
references.pmid: 22310713
references.citation: Circ J. 2011;75(12):2853-61
references.pmid: 21963570
references.citation: Blood. 2013 Feb 7;121(6):918-29
references.pmid: 23134786
references.citation: Biochem J. 2012 Mar 1;442(2):253-62
references.pmid: 22329799
references.citation: Circ Res. 2010 May 28;106(10):1559-69
references.pmid: 20508200
references.citation: PLoS One. 2009 Jun 29;4(6):e6054
references.pmid: 19562077
references.citation: Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1104-11
references.pmid: 19407244
references.citation: Circulation. 2001 Jan 16;103(2):276-83
references.pmid: 11208689
references.citation: Nat Rev Immunol. 2011 Oct 25;11(11):750-61
references.pmid: 22025054
references.citation: J Am Coll Cardiol. 2011 Jul 12;58(3):248-55
references.pmid: 21737014
references.citation: Int Immunol. 2009 Mar;21(3):295-301
references.pmid: 19181931
references.citation: J Immunol. 2010 Oct 1;185(7):4363-73
references.pmid: 20739676
references.citation: J Immunol. 2010 Jan 15;184(2):550-4
references.pmid: 20008296
references.citation: Pancreas. 2010 Aug;39(6):897-903
references.pmid: 20182391
references.citation: Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1419-23
references.pmid: 19696407
references.citation: J Clin Invest. 2007 Jan;117(1):195-205
references.pmid: 17200719
references.citation: J Clin Hypertens (Greenwich). 2009 Dec;11(12):761-5
references.pmid: 20021538
references.citation: Cell Adh Migr. 2007 Jul-Sep;1(3):133-6
references.pmid: 19262131
references.citation: Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2062-8
references.pmid: 16123319
references.citation: Circulation. 2009 May 26;119(20):2686-92
references.pmid: 19433762
references.citation: Circ Res. 2007 Jun 8;100(11):1546-55
references.pmid: 17556668
references.citation: Circ J. 2011;75(6):1305-13
references.pmid: 21566338
references.citation: Circulation. 2005 Oct 25;112(17):2708-15
references.pmid: 16230484
references.citation: Nat Clin Pract Cardiovasc Med. 2008 Feb;5(2):91-102
references.pmid: 18223541
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:3094-110
references.pmid: 19273260
references.citation: Curr Hypertens Rep. 2003 Oct;5(5):393-401
references.pmid: 12948432
references.citation: Circulation. 2007 Jun 12;115(23):2948-56
references.pmid: 17533181
references.citation: Oncogene. 2008 Sep 1;27(38):5132-7
references.pmid: 18758482
references.citation: Am J Med Sci. 2005 Dec;330(6):311-8
references.pmid: 16355016
references.citation: Immunity. 2010 Jan 29;32(1):14-27
references.pmid: 20152168
references.citation: Trends Immunol. 2009 Oct;30(10):475-87
references.pmid: 19781994
references.citation: Nature. 2006 Dec 21;444(7122):1032-7
references.pmid: 17183313
references.citation: Immunol Lett. 2008 Dec 22;121(2):140-7
references.pmid: 19027794
references.citation: Cardiovasc Pathol. 1994 Apr-Jun;3(2):81-5
references.pmid: 25990852
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: Cardiovasc Pathol. 2004 May-Jun;13(3):125-38
references.pmid: 15081469
references.citation: J Clin Invest. 2006 Jun;116(6):1494-505
references.pmid: 16691291
references.citation: Hypertension. 2010 Mar;55(3):579-92
references.pmid: 20101002
references.citation: Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):685-91
references.pmid: 18239153
references.citation: Hepatology. 2004 Apr;39(4):1056-65
references.pmid: 15057910
references.citation: J Clin Invest. 2007 Jan;117(1):185-94
references.pmid: 17200718
references.citation: Nat Rev Genet. 2008 Jan;9(1):49-61
references.pmid: 18071321
references.citation: Nat Rev Cancer. 2011 May;11(5):338-51
references.pmid: 21508972
references.citation: Nature. 2005 Jun 16;435(7044):964-8
references.pmid: 15959516
references.citation: Blood. 2006 Feb 1;107(3):931-9
references.pmid: 16219802
references.citation: Circulation. 2012 Jan 3;125(1):9-11
references.pmid: 22090164
references.citation: Lancet. 2005 Apr 16-22;365(9468):1415-28
references.pmid: 15836891
references.citation: Nat Med. 2002 Nov;8(11):1257-62
references.pmid: 12411953
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Circulation. 2004 Oct 5;110(14):1953-9
references.pmid: 15451791
references.citation: Circulation. 2009 Apr 7;119(13):1785-94
references.pmid: 19307473
references.citation: Development. 2007 Aug;134(15):2709-18
references.pmid: 17611219
references.citation: Pathophysiol Haemost Thromb. 2006;35(1-2):58-62
references.pmid: 16855348
references.citation: Biochem Biophys Res Commun. 2009 Apr 17;381(4):654-9
references.pmid: 19250926
references.citation: Circ J. 2005 Dec;69(12):1484-9
references.pmid: 16308496
references.citation: J Clin Invest. 2006 Jan;116(1):115-24
references.pmid: 16341265
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15949-54
references.pmid: 15520367
references.citation: Clin Cancer Res. 2007 Dec 15;13(24):7243-6
references.pmid: 18094402