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Protective effects of trehalose preconditioning on cardiac and coronary endothelial function through eNOS signaling pathway in a rat model of ischemia–reperfusion injury

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Abstract

Coronary endothelial dysfunction is a major cause of ischemia–reperfusion (I/R) injury. Trehalose, a natural disaccharide, has been reported to ameliorate endothelial dysfunction during aging by activating endothelial nitric oxide synthase (eNOS); however, its role in I/R injury is unknown. This study evaluated the effects of trehalose preconditioning on cardiac and coronary endothelial function after I/R. Langendorff-perfused rat hearts underwent 30 min of global ischemia followed by 80 min of reperfusion with or without trehalose preconditioning. Rate pressure product (RPP) and coronary flow (CF) were measured during reperfusion. Perivascular edema was assessed by hematoxylin and eosin staining. Myocardial oxidative stress and apoptosis were evaluated by immunohistochemistry and TUNEL staining, respectively. eNOS dimerization was determined by western blotting. An eNOS inhibitor was used to examine the role of eNOS. Trehalose preconditioning showed a higher recovery rate after I/R as indicated by high RPP (control vs. trehalose, 28 ± 6% vs. 46 ± 9%; P = 0.017, Cohen’s d = 2.3) and CF values (35 ± 10% vs. 55 ± 9%; P = 0.025, d = 1.7). Furthermore, trehalose preconditioning reduced perivascular edema, myocardial oxidative stress, and apoptosis. The eNOS dimerization ratio was increased by trehalose (1.2 ± 0.2 vs. 1.6 ± 0.2; P = 0.023, d = 2.1), which was associated with the recovery of RPP and CF. These effects of trehalose were abolished by the eNOS inhibitor. Trehalose preconditioning showed protective effects on cardiac and coronary endothelial function after I/R through the eNOS signaling pathway.

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The datasets generated during the current study will be shared on reasonable request to the corresponding author.

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Acknowledgements

The authors thank Editage for English language editing. We also thank Sapporo General Pathology Laboratory for technical assistance with the experiments.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Cardiovascular and Thoracic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kitaku, Sapporo, 060-8638, Japan

    Kenichiro Suno, Yasushige Shingu & Satoru Wakasa

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  1. Kenichiro Suno
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  2. Yasushige Shingu
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by KS and YS. Manuscript revision was performed by SW. The first draft of the manuscript was written by KS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yasushige Shingu.

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All applicable international and national guidelines for the care and use of animals were followed. And all experimental procedures were conducted according to the Hokkaido university manual for implementing animal experimentation. No human studies were carried out by the authors for this article.

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Suno, K., Shingu, Y. & Wakasa, S. Protective effects of trehalose preconditioning on cardiac and coronary endothelial function through eNOS signaling pathway in a rat model of ischemia–reperfusion injury. Mol Cell Biochem 477, 2403–2414 (2022). https://doi.org/10.1007/s11010-022-04451-y

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