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. 2019 Feb;234(2):1671-1681.
doi: 10.1002/jcp.27037. Epub 2018 Sep 1.

Irisin promotes cardiac progenitor cell-induced myocardial repair and functional improvement in infarcted heart

Yu Tina Zhao  1 , Jianguo Wang  1 , Naohiro Yano, Ling X Zhang  2 , Hao Wang  1 , Shouyan Zhang  3 , Gangjian Qin  4 , Patrycja M Dubielecka  2 , Shougang Zhuang  2 , Paul Y Liu  5 , Y Eugene Chin  6 , Ting C Zhao  1
Affiliations

Irisin promotes cardiac progenitor cell-induced myocardial repair and functional improvement in infarcted heart

Yu Tina Zhao et al. J Cell Physiol. 2019 Feb.

Abstract

Irisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)-induced cardiac repair remains unknown. This study examines the effect of irisin on CPC-induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5+ CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5 + CPCs (0.5 × 10 6 ) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5 + CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5 + CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5 + CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5 + CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5 + CPC-induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair.

Keywords: cardiac progenitor cell; irisin; myocardial infarction; ventricular function.

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Conflict of interest statement

Conflict of interests:

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Echocardiographic measurements of ventricular function
(a) Echocardiographic measurements of ventricular functional parameter: ejection fraction (EF) and fractional shortening (FS). (b) Representative images are shown as the M-mode short-axis ultrasound among groups. (c and d): Left ventricular internal diameter at systole (LVIDs) and left ventricular internal diameter at diastole (LVIDd). Values represent mean ± SE (n = 4 – 7/per group).
Figure 2
Figure 2. Irisin pre-treatment promotes differentiations of CPCs into cardiomyocytes and smooth-muscle cells of vessels
(a) Representative images showing localization of CPC derived cardiomyocytes in MI receiving CPC treatments among groups (GFP, troponin T double positive cells); TNT: troponin T; scale bars in pictures indicate 10 μm. (b) Representative images showing localization and comparison of the CPC derived smooth muscle of vessels in MI receiving CPC treatments among groups (GFP, SMA double positive cells); scale bars in pictures indicate 100 μm. (c) Quantification of CPC derived cardiomyocytes in the infarcted area. (d) Quantification of CPC derived smooth muscle cells of vessels in the infarcted area. Values in the bar graphs represent means ± SE (n = 4-5 hearts/per group).
Figure 3
Figure 3. Irisin attenuates hypertrophy of cardiomyocytes due to ischemic damages
(a) Representative image of WGA staining of cardiomyocytes from sham, MI, MI + CPC, and MI + CPC + irisin group of mice. (b) A graph for cross sectional areas of each group. Values represent means ± SE. Scale bars in pictures indicate 100 μm. (n = 4 – 5/per group).
Figure 4
Figure 4. Irisin promotes angiogenesis after CPC transplantation in infarcted heart
(a) Representative image of CD31 of vessel endothelial cells in sham, MI, MI + CPC, and MI + CPC + irisin group of mice. Scale bars in picture indicate 100 μm. (b) A graph for the number of CD31 positive cells in the infarcted heart. Values represent means ± SE. (n = 4 – 5/per group).
Figure 5
Figure 5. Comparison of interstitial fibrosis deposition in MI hearts
(a) Representative images showing picrosirius red staining in sham, MI, MI + PCP, and MI + CPC + irisin group mice. Scale bars in picture indicates 100 μm. (b) Quantitative analysis of interstitial fibrotic area. Values represent mean ± SE. (n = 3-5/per group).
Figure 6
Figure 6. Dual immunofluorescent staining of phospho-histone 3 and Ki67 with cardiomyocyte
Representative images of phospho-histone 3 (a) and Ki67 (b) staining in MI, MI + PCP, and MI + CPC + irisin group mice. Scale bars in picture indicate 10μm. Quantitative analysis of the numbers of phospho-histone 3 positive cells (c) and Ki67 positive cells (d) per field, TNT: troponin T. Values represent mean ± SE. (n = 4-5/per group).
Figure 7
Figure 7. Irisin attenuated apoptotic myocytes in CPC-engrafted MI heart
a: Representative images of TUNEL staining (Green: TUNEL positive staining; red: troponin T; blue: DAPI); b: Quantitative analysis of TUNEL positive signals in the post-MI heart. Values are shown as mean ± SEM (n = 3-5 per group). Scale bar: 10μm
Figure 8
Figure 8. Western blot showing active caspase 3, HDAC4 and acetylated p38 in Nkx2.5+CPCs
(a) Representative Western blot showing the effect of irisin on the content of active caspase 3 and quantification of densitometry of gels among individual groups (n=3 per group), Values are shown as mean ± SEM, *p<0.05 vs control group; (b) Representative Western blot showing the effect of irisin on the content of HDAC4 and densitometry of gels among individual groups (n=3 per group),; *p<0.05 vs control group; (c) Representative Western blot showing the effect of irisin on the content of acetylated p38 and quantification of densitometry of gels among individual groups (n=3 per group), *p<0.05 vs control group; IgG serves as control.
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References

    1. Aydin S, Aydin S, Kobat MA, Kalayci M, Eren MN, Yilmaz M, Kuloglu T, Gul E, Secen O, Alatas OD, Baydas A. Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology. Peptides. 2014;56:141–5. - PubMed
    1. Anastasilakis CD, Mantzoros CS. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Metabolism. 2017;73:1–8. - PubMed
    1. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8. - PMC - PubMed
    1. Chen HP, Denicola M, Qin X, Zhao Y, Zhang L, Long XL, Zhuang S, Liu PY, Zhao TC. HDAC inhibition promotes cardiogenesis and the survival of embryonic stem cells through proteasome-dependent pathway. J Cell Biochem. 2011;112:3246–55. - PMC - PubMed
    1. Finegold JA, Asaria P, Francisa DP. Mortality from ischaemic heart disease by country, region, and age: Statistics from World Health Organisation and United Nations. Int J Cardiol. 2013;168:934–945. - PMC - PubMed

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