title: Fortilin reduces apoptosis in macrophages and promotes atherosclerosis.
abstract: Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient (fortilin(+/-)) mice and wild-type counterparts (fortilin(+/+)) on a LDL receptor (Ldlr)(-/-) apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)(-/-) hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin(+/-) mice exhibited significantly less atherosclerosis in their aortae than their fortilin(+/+) littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin(+/-) mice contained fewer macrophages than those of fortilin(+/+) mice. In addition, there were more apoptotic cells in the intima of fortilin(+/-) mice than in the intima of fortilin(+/+) mice. Furthermore, peritoneal macrophages from fortilin(+/-) mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr(-/-)Apobec1(-/-) mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Decha
authors.initials: D
authors.lastname: Pinkaew
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Le
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Eltorky
authors.forename: Ba-Bie
authors.initials: BB
authors.lastname: Teng
authors.forename: Ken
authors.initials: K
authors.lastname: Fujise
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000090324:Tumor Protein, Translationally-Controlled 1; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D014408:Biomarkers, Tumor; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000090324:Tumor Protein, Translationally-Controlled 1; D051028:bcl-2-Associated X Protein; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase
keywords: apoptosis; atherosclerosis; fortilin; macrophages
references.citation: J Biol Chem. 1996 Oct 18;271(42):25981-8
references.pmid: 8824235
references.citation: Transgenic Res. 2012 Dec;21(6):1245-54
references.pmid: 22415346
references.citation: J Biol Chem. 2011 Sep 16;286(37):32575-85
references.pmid: 21795694
references.citation: J Biol Chem. 2004 Oct 29;279(44):46104-12
references.pmid: 15319436
references.citation: Nat Med. 2013 Sep;19(9):1166-72
references.pmid: 23933982
references.citation: Circulation. 2003 Jul 29;108(4):464-71
references.pmid: 12860918
references.citation: J Biol Chem. 2004 Sep 24;279(39):40868-75
references.pmid: 15262975
references.citation: FEBS Lett. 2008 Apr 2;582(7):1055-60
references.pmid: 18325342
references.citation: Biochim Biophys Acta. 2009 Jan 1;1790(1):31-9
references.pmid: 18930785
references.citation: Circulation. 2000 May 16;101(19):2290-5
references.pmid: 10811597
references.citation: Nat Med. 1999 Mar;5(3):335-9
references.pmid: 10086392
references.citation: Circ Res. 2001 Apr 27;88(8):747-9
references.pmid: 11325863
references.citation: Nature. 2008 Feb 21;451(7181):904-13
references.pmid: 18288179
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):174-9
references.pmid: 15499039
references.citation: Nat Med. 2011 Nov 07;17(11):1410-22
references.pmid: 22064431
references.citation: J Clin Invest. 2005 Feb;115(2):359-68
references.pmid: 15650769
references.citation: Nature. 2007 Feb 15;445(7129):785-8
references.pmid: 17301792
references.citation: J Am Coll Cardiol. 2000 Mar 1;35(3):655-65
references.pmid: 10716468
references.citation: Biochem J. 2007 Dec 1;408(2):181-91
references.pmid: 17705784
references.citation: J Biol Chem. 2001 Dec 14;276(50):47542-9
references.pmid: 11598139
references.citation: FASEB J. 2001 Sep;15(11):1989-95
references.pmid: 11532979
references.citation: N Engl J Med. 2007 Nov 22;357(21):2109-22
references.pmid: 17984165
references.citation: Arch Pharm Res. 2000 Dec;23(6):633-6
references.pmid: 11156187
references.citation: Arterioscler Thromb Vasc Biol. 1998 May;18(5):794-802
references.pmid: 9598839
references.citation: FEBS J. 2009 May;276(10):2752-61
references.pmid: 19389115
references.citation: J Clin Invest. 2008 Mar;118(3):984-93
references.pmid: 18274671
references.citation: Mol Biol Cell. 2007 Jul;18(7):2525-32
references.pmid: 17475776
references.citation: JAMA. 2007 Sep 12;298(10):1189-95
references.pmid: 17848653
references.citation: Methods Mol Biol. 2003;209:293-309
references.pmid: 12357958
references.citation: Blood. 2009 Mar 19;113(12):2805-15
references.pmid: 19064728
references.citation: Cell. 1998 Apr 17;93(2):241-52
references.pmid: 9568716
references.citation: J Clin Invest. 1993 Aug;92(2):883-93
references.pmid: 8349823
references.citation: J Lipid Res. 1995 Nov;36(11):2320-8
references.pmid: 8656070
references.citation: Mol Cell Biol. 2002 Sep;22(17):6209-21
references.pmid: 12167714
references.citation: Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1608-14
references.pmid: 12842843
references.citation: Cell Metab. 2005 Apr;1(4):223-30
references.pmid: 16054067
references.citation: Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E284-90
references.pmid: 18029445
references.citation: Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91
references.pmid: 16179593
references.citation: Science. 1995 Aug 4;269(5224):688-90
references.pmid: 7542803
references.citation: FASEB J. 1998 Apr;12(6):461-7
references.pmid: 9535218
references.citation: J Lipid Res. 2005 Feb;46(2):211-9
references.pmid: 15547296
references.citation: Eur J Biochem. 2000 Oct;267(19):6050-9
references.pmid: 10998066
references.citation: Nat Med. 1998 Aug;4(8):934-8
references.pmid: 9701246
references.citation: Cardiovasc Res. 1998 Jul;39(1):8-33
references.pmid: 9764187
references.citation: J Biol Chem. 2002 Oct 4;277(40):37430-8
references.pmid: 12149273
references.citation: Biochim Biophys Acta. 2009 May;1790(5):326-38
references.pmid: 19364479
references.citation: Circulation. 2003 Jan 7;107(1):98-105
references.pmid: 12515750
references.citation: Circ Res. 2001 Apr 27;88(8):780-6
references.pmid: 11325869
references.citation: J Immunol Methods. 1997 Sep 24;207(2):157-68
references.pmid: 9368642
references.citation: J Mol Cell Cardiol. 2008 Jan;44(1):151-9
references.pmid: 17976639
references.citation: Circulation. 2011 Feb 1;123(4):e18-e209
references.pmid: 21160056
references.citation: Science. 1992 Oct 16;258(5081):468-71
references.pmid: 1411543
references.citation: Atherosclerosis. 1999 Jul;145(1):33-43
references.pmid: 10428293
references.citation: J Clin Invest. 2012 Jan;122(1):218-28
references.pmid: 22133880
references.citation: Nucleic Acids Res. 1989 Oct 25;17(20):8367
references.pmid: 2813067
references.citation: Atherosclerosis. 2010 Nov;213(1):40-51
references.pmid: 20667539
references.citation: Atherosclerosis. 2003 Jul;169(1):51-62
references.pmid: 12860250
references.citation: JAMA. 2008 Apr 2;299(13):1547-60
references.pmid: 18387931