Antagonist of sphingosine 1-phosphate receptor 3 reduces cold injury of rat donor hearts for transplantation.
Antagonist of sphingosine 1-phosphate receptor 3 reduces cold injury of rat donor hearts for transplantation.
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DOI：
10.1016/j.trsl.2022.11.003
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发表时间：
2022-11
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通讯作者：
Eisho Kanemitsu;Xiangdong Zhao;K. Iwaisako;A. Inoue;A. Takeuchi;S. Yagi;H. Masumoto;Hiroaki Ohara;Motoyasu Hosokawa;T. Awaya;J. Aoki;E. Hatano;S. Uemoto;M. Hagiwara
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作者：
Eisho Kanemitsu;Xiangdong Zhao;K. Iwaisako;A. Inoue;A. Takeuchi;S. Yagi;H. Masumoto;Hiroaki Ohara;Motoyasu Hosokawa;T. Awaya;J. Aoki;E. Hatano;S. Uemoto;M. Hagiwara
冷藏广泛用于保存移植器官;然而，长时间的冷藏会对移植功能产生负面影响。不幸的是，冷暴露的潜在机制仍不清楚。基于鞘氨醇-1-磷酸（S1 P）信号参与冬眠哺乳动物的耐冷性，我们假设S1 P信号阻断减少了冷藏的损害。本研究采用离体冷藏复温模型评价冷损伤，并探讨冷损伤与S1 P信号的关系。筛选影响S1 P受体（S1 PR）的化合物在该模型中的保护作用，并使用NanoLuc二元技术（NanoBiT）-β-抑制蛋白募集试验测量其对S1 PR的抑制作用。通过异位腹部大鼠心脏移植检查有效拮抗剂的作用。保存24小时后移植心脏，并在移植后第7天进行评估。冷害随冷藏时间的延长而增加，且由S1 P诱导。最有效的拮抗剂强烈抑制冷损伤与体外S1 P剥夺的效果一致。在体内，这种拮抗剂使24小时的保存，并大大提高了跳动的分数，心脏的大小，和血清学标志物。病理学分析显示，其抑制间质水肿、炎性细胞浸润、心肌细胞损伤、TUNEL阳性细胞死亡和纤维化。总之，S1 PR 3拮抗剂减少了冷损伤，延长了冷保存时间，提高了移植物的活力。通过S1 P信号传导的冷保存策略可能在移植器官保存中具有临床应用，并有助于增加供体库。翻译的意义我们专注于鞘氨醇-1-磷酸（S1 P）参与冬眠哺乳动物的耐寒性，并确定了一种新的S1 P受体3拮抗剂，保护大鼠移植心脏免受冷损伤。这种拮抗剂可以有效地作为器官保存溶液，延长移植器官的冷藏时间，改善器官移植治疗的结果。
Cold storage is widely used to preserve an organ for transplantation; however, a long duration of cold storage negatively impacts graft function. Unfortunately, the mechanisms underlying cold exposure remain unclear. Based on the sphingosine-1-phosphate (S1P) signal involved in cold tolerance in hibernating mammals, we hypothesized that S1P signal blockage reduces damage from cold storage. We used an in vitro cold storage and rewarming model to evaluate cold injury and investigated the relationship between cold injury and S1P signal. Compounds affecting S1P receptors (S1PR) were screened for their protective effect in this model and its inhibitory effect on S1PRs was measured using the NanoLuc Binary Technology (NanoBiT)-β-arrestin Recruitment Assays. The effects of a potent antagonist were examined via heterotopic abdominal rat heart transplantation. The heart grafts were transplanted after 24-h preservation and evaluated on day 7 after transplantation. Cold injury increased depending on the cold storage time and was induced by S1P. The most potent antagonist strongly suppressed cold injury consistent with the effect of S1P deprivation in vitro. In vivo, this antagonist enabled 24-h preservation, and drastically improved the beating score, cardiac size, and serological markers. Pathological analysis revealed that it suppressed the interstitial edema, inflammatory cell infiltration, myocyte lesion, TUNEL-positive cell death, and fibrosis. In conclusion, S1PR3 antagonist reduced cold injury, extended the cold preservation time, and improved graft viability. Cold preservation strategies via S1P signaling may have clinical applications in organ preservation for transplantation and contribute to an increase in the donor pool.BackgroundFor organ transplantation, the cold storage time of a harvested heart is limited, that is, only 4–6 h. This leads to a decrease in the utilization of the donor graft.Translational SignificanceWe focused on sphingosine-1-phosphate (S1P) involved in the cold tolerance of hibernating mammals and identified a novel S1P receptor 3 antagonist that protected the rat graft heart from cold injury. This antagonist could be effective as an organ preservation solution that extends the cold storage time of graft organs and improves the outcome of organ transplantation therapy.