Irisin Inhibits Atherosclerosis by Promoting Endothelial Proliferation Through microRNA126-5p.
BACKGROUND
Irisin is a newly discovered myokine that has been considered a promising candidate for the treatment of cardiovascular disease through improving endothelial function. However, little is known about the role of irisin in the progression of atherosclerosis.


RESULTS
We used a carotid partial ligation model of apolipoprotein E-deficient mice fed on a high-cholesterol diet to test the anti-atherosclerosis effect of irisin. Irisin treatment significantly suppressed carotid neointima formation. It was associated with increased endothelial cell proliferation. In addition, irisin promoted human umbilical vein endothelial cell survival via upregulating microRNA126-5p expression through the ERK signaling pathway. Inhibition of microRNA126-5p using the microRNA126-5p inhibitor abolished the prosurvival effect. The same results were demonstrated in vivo as the expression of microRNA126-5p noticeably increased in ligated carotid artery after irisin treatment. Furthermore, in vivo blockade of microRNA126-5p expression using the antagomir abolished the inhibitory effects of irisin on neointima formation, lesional lipid deposition, macrophage area, and the pro-proliferation effects on endothelial cells.


CONCLUSIONS
Taken together, our study demonstrates that irisin significantly reduces atherosclerosis in apolipoprotein E-deficient mice via promoting endothelial cell proliferation through microRNA126-5p, which may have a direct therapeutic effect on atherosclerotic diseases.
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Yuzhu
Y
Zhang
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Haibo
H
Song
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Yuan
Y
Zhang
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Fei
F
Wu
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Qian
Q
Mu
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Miao
M
Jiang
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Fang
F
Wang
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Wen
W
Zhang
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Liang
L
Li
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
Lei
L
Shao
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Shiwu
S
Li
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Lijun
L
Yang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.
Mingxiang
M
Zhang
Department of Anatomy, School of Medicine Shandong University, Jinan, China.
Qi
Q
Wu
Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China tangdq@sdu.edu.cn.
Dongqi
D
Tang
atherosclerosis; endothelial cells; irisin; microRNA126‐5p
Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1501-8
26371167
Biochem Biophys Res Commun. 2015 Dec 25;468(4):832-6
26582714
Clin Endocrinol (Oxf). 2015 Sep;83(3):339-43
25382211
Nature. 2011 Jan 20;469(7330):336-42
21248840
J Diabetes Complications. 2013 Jul-Aug;27(4):365-9
23619195
Sci Rep. 2015 Oct 13;5:15132
26459935
Diabetes. 2014 Feb;63(2):514-25
24150604
Circulation. 2007 Mar 13;115(10):1285-95
17353456
Eur Cytokine Netw. 1998 Dec;9(4):697-8
9889419
J Clin Endocrinol Metab. 2013 Dec;98(12):4899-907
24057291
PLoS One. 2016 Jun 29;11(6):e0158038
27355581
Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1100-5
12117723
Nat Cell Biol. 2013 Mar;15(3):284-94
23396050
Cell Metab. 2015 Oct 6;22(4):734-40
26278051
Nature. 2000 Sep 14;407(6801):233-41
11001066
Cardiovasc Res. 2014 Jun 1;102(3):436-47
24562769
Dev Cell. 2008 Aug;15(2):272-84
18694566
Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1725-32
20558819
Cardiovasc Res. 2013 Jul 15;99(2):294-303
23612583
Atherosclerosis. 2014 Aug;235(2):328-33
24911636
Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1535-43
19684185
Peptides. 2013 Jan;39:125-30
23219488
Circ Res. 2014 Jan 3;114(1):3-4
24385499
Nature. 2012 Jan 11;481(7382):463-8
22237023
Nat Med. 2014 Apr;20(4):368-76
24584117
Cell. 2004 Jan 23;116(2):281-97
14744438
Annu Rev Pathol. 2009;4:71-95
18754744
Sci Rep. 2016 Jan 07;6:18732
26738434
Sci Rep. 2014 Jul 01;4:5519
24980430
Circulation. 2009 Oct 13;120(15):1524-32
19786632
Can J Physiol Pharmacol. 2012 Jun;90(6):713-38
22625870
PLoS One. 2014 Oct 22;9(10):e110273
25338001
Nature. 2002 Dec 19-26;420(6917):868-74
12490960
Curr Atheroscler Rep. 2013 Dec;15(12):372
24158362
PLoS One. 2013;8(2):e56824
23437250
FASEB J. 2011 Aug;25(8):2515-27
21507901
Cardiovasc Res. 2012 Feb 1;93(2):232-41
22068159
J Mol Cell Cardiol. 2015 Oct;87:138-47
26225842
PLoS One. 2015 Aug 04;10(8):e0134662
26241478
Heart. 2012 Feb;98 (3):177-84
22095617