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Remote ischemic preconditioning reduces myocardial ischemia–reperfusion injury through unacylated ghrelin-induced activation of the JAK/STAT pathway

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Abstract

Remote ischemic preconditioning (RIPC) offers cardioprotection against myocardial ischemia–reperfusion injury. The humoral factors involved in RIPC that are released from parasympathetically innervated organs have not been identified. Previous studies showed that ghrelin, a hormone released from the stomach, is associated with cardioprotection. However, it is unknown whether or not ghrelin is involved in the mechanism of RIPC. This study aimed to determine whether ghrelin serves as one of the humoral factors in RIPC. RIPC group rats were subjected to three cycles of ischemia and reperfusion for 5 min in two limbs before left anterior descending (LAD) coronary artery ligation. Unacylated ghrelin (UAG) group rats were given 0.5 mcg/kg UAG intravenously 30 min before LAD ligation. Plasma levels of UAG in all groups were measured before and after RIPC procedures and UAG administration. Additionally, JAK2/STAT3 pathway inhibitor (AG490) was injected in RIPC and UAG groups to investigate abolishment of the cardioprotection of RIPC and UAG. Plasma levels of UAG, infarct size and phosphorylation of STAT3 were compared in all groups. Infarct size was significantly reduced in RIPC and UAG groups, compared to the other groups. Plasma levels of UAG in RIPC and UAG groups were significantly increased after RIPC and UAG administration, respectively. The cardioprotective effects of RIPC and UAG were accompanied by an increase in phosphorylation of STAT3 and abolished by AG490. This study indicated that RIPC reduces myocardial ischemia and reperfusion injury through UAG-induced activation of JAK/STAT pathway. UAG may be one of the humoral factors involved in the cardioprotective effects of RIPC.

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Acknowledgements

The authors would like to thank Keiko Onishi, and Yuri Horiguchi, research technologists (Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan), for their technical assistance.

Funding

This study was supported by Grant-in-Aid for Early-Career Scientists (Grant no. 18K16486) from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan

    Yasuaki Sawashita, Naoyuki Hirata, Yusuke Yoshikawa, Hirofumi Terada, Yasuyuki Tokinaga & Michiaki Yamakage

Authors
  1. Yasuaki Sawashita
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  2. Naoyuki Hirata
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  3. Yusuke Yoshikawa
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  4. Hirofumi Terada
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  5. Yasuyuki Tokinaga
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  6. Michiaki Yamakage
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Contributions

YS wrote the manuscript; YS performed the animal studies; NH, YY, HT and YT helped the animal studies; NH and MY reviewed and edited the manuscript.

Corresponding author

Correspondence to Yasuaki Sawashita.

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Conflict of interest

None of the authors declare any competing interests.

Ethics approval

This animal study was approved by the Institutional Animal Care and Use Committee of Sapporo Medical University (No. 17-117,118).

Electronic supplementary material

Below is the link to the electronic supplementary material.

395_2020_809_MOESM1_ESM.tif

Online resource 1: Plasma concentrations of acylated ghrelin in control and RIPC groups. Blood samples in the two groups were collected pre and post the RIPC procedure. Data are shown as mean (pg/mL) ± SEM, n = 8 rats per group. No significant differences were observed by two-way ANOVA followed by Tukey post hoc test (TIF 57 kb)

395_2020_809_MOESM2_ESM.tif

Online resource 2: The result of all Western blot of the STAT3tyr705 phosphorylation in rat myocardium m. Data are shown numerically as the ratio of phosphorylated STAT3 and total STAT3 (TIF 225 kb)

395_2020_809_MOESM3_ESM.tif

Online resource 3: Plasma concentrations of unacylated ghrelin (UAG) after administration of various UAG doses. Blood samples in each group were collected before and 30 minutes after administration of UAG. Data are shown as mean (pg/mL) ± SEM, n = 8 rats per group. *: P < 0.05 vs. ‘pre’ in each group, as assessed by two-way ANOVA followed by Tukey post hoc test. Abbreviations: pre, before UAG administration; post, 30 minutes after UAG administration; CON, control group; UAG 0.25, 0.25 mcg/kg UAG administration group; UAG 0.5, 0.5 mcg/kg UAG administration group; UAG 1, 1 mcg/kg UAG administration group (TIF 59 kb)

395_2020_809_MOESM4_ESM.tif

Online resource 4: Area at risk in the seven groups. The area at risk is presented as a percentage of the left ventricle. Data are shown as mean % ± SEM, n = 8 rats per group. No significant difference was observed between groups, as assessed by one-way ANOVA followed by Tukey post hoc test. Abbreviations: CON, control group; UAG, unacylated ghrelin; UAG 0.25, 0.25 mcg/kg UAG administration group; UAG 0.5, 0.5 mcg/kg UAG administration group; UAG 1, 1 mcg/kg UAG administration group; UAG 2, 2 mcg/kg UAG administration group; UAG 20, 20 mcg/kg UAG administration group; UAG 30, 30 mcg/kg UAG administration group (TIF 70 kb)

395_2020_809_MOESM5_ESM.tif

Online resource 5: Infarct size in the seven groups. Infarct size is presented as a percentage of the area at risk. Data are shown as mean % ± SEM, n = 8 rats per group. *: P < 0.05 vs. CON, †: P < 0.05 vs. UAG 0.25 as assessed by one-way ANOVA followed by Tukey post hoc test. Abbreviations: CON, control group; UAG, unacylated ghrelin; UAG 0.25, 0.25 mcg/kg UAG administration group; UAG 0.5, 0.5 mcg/kg UAG administration group; UAG 1, 1 mcg/kg UAG administration group; UAG 2, 2 mcg/kg UAG administration group; UAG 20, 20 mcg/kg UAG administration group; UAG 30, 30 mcg/kg UAG administration group (TIF 71 kb)

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Sawashita, Y., Hirata, N., Yoshikawa, Y. et al. Remote ischemic preconditioning reduces myocardial ischemia–reperfusion injury through unacylated ghrelin-induced activation of the JAK/STAT pathway. Basic Res Cardiol 115, 50 (2020). https://doi.org/10.1007/s00395-020-0809-z

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