Leguina-Ruzzi Alberto, Ortiz Diban Rina, Velarde Victoria
Juntendo University, School of Medicine, Tokyo 113-8431, Japan.
Institute of Physiology AS CR, v.v.l. Department of Mitochondrial Physiology, 14220 Prague, Czech Republic.
Med Sci (Basel). 2019 Apr 24;7(4):65. doi: 10.3390/medsci7040065.
Type 2 diabetes affects over 340 million people worldwide. This condition can go unnoticed and undiagnosed for years, leading to a late stage where high glycaemia produces complications such as delayed wound healing. Studies have shown that 12-HHT through BLT2, accelerates keratinocyte migration and wound healing. Additionally, evidence has shown the role of nitric oxide as a pro-regenerative mediator, which is decreased in diabetes. Our main goal was to study the association between the 12-HHT/BLT2 axis and the nitric oxide production in wound healing under different glycaemia conditions. For that purpose, we used in vivo and in vitro models. Our results show that the skin from diabetic mice showed reduced BLT2 and iNOS mRNA, TEER, 12-HHT, nitrites, and tight junction levels, accompanied by higher MMP9 mRNA levels. Furthermore, a positive correlation between BLT2 mRNA and nitrites was observed. In vitro, HaCaT-BLT2 cells showed higher nitric oxide and tight junction levels, and reduced MMP9 mRNA levels, compared to mock-keratinocytes under low and high glucose condition. The wound healing capacity was associated with higher nitric oxide production and was affected by the NOS inhibition. We suggest that the BLT2 expression improves the keratinocyte response to hyperglycaemia, associated with the production of nitric oxide.
2型糖尿病影响着全球超过3.4亿人。这种疾病可能多年未被察觉和诊断，导致晚期出现高血糖引发的并发症，如伤口愈合延迟。研究表明，12 - HHT通过BLT2可加速角质形成细胞迁移和伤口愈合。此外，有证据表明一氧化氮作为一种促再生介质，在糖尿病患者中含量降低。我们的主要目标是研究在不同血糖条件下，12 - HHT/BLT2轴与伤口愈合过程中一氧化氮产生之间的关联。为此，我们使用了体内和体外模型。我们的结果显示，糖尿病小鼠的皮肤中BLT2和诱导型一氧化氮合酶（iNOS）mRNA、跨上皮电阻（TEER）、12 - HHT、亚硝酸盐和紧密连接水平降低，同时基质金属蛋白酶9（MMP9）mRNA水平升高。此外，观察到BLT2 mRNA与亚硝酸盐之间存在正相关。在体外，与低葡萄糖和高葡萄糖条件下的mock - 角质形成细胞相比，HaCaT - BLT2细胞显示出更高的一氧化氮和紧密连接水平，以及更低的MMP9 mRNA水平。伤口愈合能力与更高的一氧化氮产生相关，并受到一氧化氮合酶抑制的影响。我们认为，BLT2表达改善了角质形成细胞对高血糖的反应，这与一氧化氮的产生有关。
