title: Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE(-/-) mice.
abstract: Fibroblast growth factor 21 (FGF-21) is an endocrine factor that can be secreted into circulation by the liver. FGF-21 takes part in metabolic actions and is thought to be a promising candidate for the treatment of diabetes. However, the role of FGF-21 in atherosclerosis is unknown. In this study, apoE(-/-) mice were fed an atherogenic diet for 4 weeks with and without subcutaneous injections of FGF-21. ApoE(-/-) mice fed an atherogenic diet showed hyperlipidemia, a large plaque area in aortas and increased vessel wall thickness. Plasma FGF-21 content and protein level of FGF receptor 1 (FGFR1) in aortas was greater in apoE(-/-) than C57BL/6J mice. Exogenous FGF-21 treatment significantly ameliorated dyslipidemia in apoE(-/-) mice. FGF-21-treated apoE(-/-) mice showed reduced number of aortic plaques and plaque area as well as reduced number of TUNEL-positive cells. Protein levels of the endoplasmic reticulum stress markers glucose-regulated protein 94, caspase-12 and C/EBP homologous protein were reduced by 34.5, 31.4 and 26.5 %, respectively, in apoE(-/-) mice. Endogenous expression of FGF-21 and its receptor FGFR1 were upregulated in apoE(-/-) mice, and exogenous administration of FGF-21 ameliorated the atherogenic-induced dyslipidemia and vascular atherosclerotic lesions. FGF-21 protecting against atherosclerosis might be in part by its inhibitory effects on endoplasmic reticulum stress-mediated apoptosis.
authors.affiliation: Department of Cardiology, Fuwai Hospital and National Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China. xiwu-CN@hotmail.com.|Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China. xiwu-CN@hotmail.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.|Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
authors.affiliation: Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Jin-Rui
authors.initials: JR
authors.lastname: Chang
authors.affiliation: Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Lu
authors.affiliation: Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Shao-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Man-Kun
authors.initials: MK
authors.lastname: Xin
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China. liujinghua@vip.sina.com.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Liu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency*; D017209:Apoptosis; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015153:Blotting, Western; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000627:therapeutic use; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011863:Radioimmunoassay
chemical_list: D001057:Apolipoproteins E; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: Apoptosis; Atherosclerosis; Endoplasmic reticulum stress; Fibroblast growth factor 21
references.citation: Circulation. 2004 Jun 1;109(21):2503-6
references.pmid: 15148270
references.citation: Pharmacol Ther. 2012 Jun;134(3):306-16
references.pmid: 22387231
references.citation: Nat Med. 2010 Apr;16(4):396-9
references.pmid: 20376052
references.citation: J Hum Hypertens. 2013 Jun;27(6):397-9
references.pmid: 23190795
references.citation: J Am Geriatr Soc. 2012 Apr;60(4):792-3
references.pmid: 22494291
references.citation: Heart Vessels. 2015 Jan;30(1):115-25
references.pmid: 24510253
references.citation: Circulation. 2001 Jan 23;103(3):448-54
references.pmid: 11157699
references.citation: Endocrinology. 2008 Dec;149(12):6018-27
references.pmid: 18687777
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S382-7
references.pmid: 18953058
references.citation: Cardiovasc Res. 2007 Feb 1;73(3):470-80
references.pmid: 17084825
references.citation: Nature. 2002 Dec 19-26;420(6917):868-74
references.pmid: 12490960
references.citation: Biochem Biophys Res Commun. 2007 Aug 24;360(2):437-40
references.pmid: 17601491
references.citation: J Clin Invest. 2005 Jun;115(6):1627-35
references.pmid: 15902306
references.citation: J Clin Invest. 2004 Dec;114(11):1564-76
references.pmid: 15578089
references.citation: PLoS One. 2010 Dec 29;5(12):e15534
references.pmid: 21206918
references.citation: Cell. 2012 Feb 3;148(3):556-67
references.pmid: 22304921
references.citation: Atherosclerosis. 1987 Dec;68(3):231-40
references.pmid: 3426656
references.citation: Endocrinology. 2012 Jun;153(6):2689-700
references.pmid: 22474187
references.citation: Arterioscler Thromb Vasc Biol. 2013 Oct;33(10):2306-15
references.pmid: 23887640
references.citation: Mol Endocrinol. 2010 Oct;24(10):2050-64
references.pmid: 20667984
references.citation: Clin Sci (Lond). 2004 Oct;107(4):343-54
references.pmid: 15230690
references.citation: Nitric Oxide. 2006 Dec;15(4):265-79
references.pmid: 16684613
references.citation: J Biol Chem. 2004 Nov 19;279(47):49420-9
references.pmid: 15339911
references.citation: Diabetes. 2006 Nov;55(11):3121-6
references.pmid: 17065351
references.citation: Peptides. 2013 Oct;48:21-6
references.pmid: 23927843
references.citation: Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2255-64
references.pmid: 16141399
references.citation: Cell Metab. 2009 May;9(5):474-81
references.pmid: 19416717
references.citation: Diabetes Metab J. 2012 Feb;36(1):29-36
references.pmid: 22363919
references.citation: Toxicol Lett. 2013 May 10;219(1):65-76
references.pmid: 23499715
references.citation: Nat Cell Biol. 2003 Sep;5(9):781-92
references.pmid: 12907943
references.citation: Chin Med J (Engl). 2010 Dec;123(23):3417-21
references.pmid: 22166524
references.citation: Peptides. 2010 Jun;31(6):1150-8
references.pmid: 20332006
references.citation: Circulation. 2007 Sep 11;116(11):1226-33
references.pmid: 17709641
references.citation: Cell Metab. 2010 May 5;11(5):379-89
references.pmid: 20444418
references.citation: Hypertension. 2009 Jun;53(6):1017-22
references.pmid: 19398656
references.citation: Semin Immunopathol. 2013 May;35(3):321-32
references.pmid: 23553213
references.citation: J Mol Cell Cardiol. 2010 Jun;48(6):1105-10
references.pmid: 19913545
references.citation: Nature. 2000 Sep 14;407(6801):233-41
references.pmid: 11001066
references.citation: Eur J Endocrinol. 2012 Sep;167(3):301-9
references.pmid: 22740503
references.citation: Nature. 2000 Jan 6;403(6765):98-103
references.pmid: 10638761
references.citation: Diabetes. 2009 Jan;58(1):250-9
references.pmid: 18840786
references.citation: Heart Vessels. 2014 Sep;29(5):667-78
references.pmid: 24129401
references.citation: Diabetes. 2008 May;57(5):1246-53
references.pmid: 18252893
references.citation: Circ Res. 2010 Oct 1;107(7):839-50
references.pmid: 20884885
references.citation: Semin Cell Dev Biol. 2010 Jul;21(5):479-85
references.pmid: 20223290
references.citation: Apoptosis. 2002 Aug;7(4):335-45
references.pmid: 12101393
references.citation: Metabolism. 2012 Aug;61(8):1142-51
references.pmid: 22398021
references.citation: Heart Vessels. 2015 May;30(3):286-95
references.pmid: 24519403