Melatonin Alleviates Hyperglycemia-Induced Cardiomyocyte Apoptosis via Regulation of Long Non-Coding RNA H19/miR-29c/MAPK Axis in Diabetic Cardiomyopathy.
Melatonin Alleviates Hyperglycemia-Induced Cardiomyocyte Apoptosis via Regulation of Long Non-Coding RNA H19/miR-29c/MAPK Axis in Diabetic Cardiomyopathy.
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DOI：
10.3390/ph15070821
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发表时间：
2022-07-02
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近年来的研究表明，非编码RNA（ncRNA）在糖尿病心肌病（DCM）的病理生理过程中起着重要作用，并导致心力衰竭。本研究旨在进一步研究褪黑素对糖尿病心肌细胞的抗凋亡作用，并阐明与ncRNA相关的潜在机制。在动物模型中，我们采用单次腹腔注射链脲佐菌素（STZ）溶液（55 mg/kg）的方法，在适应性喂养一周后，于晚上18：00建立SD大鼠糖尿病模型。我们的研究结果表明，褪黑激素显着减轻心功能不全和心肌细胞凋亡。在病理情况下，lncRNA H19水平增加，沿着miR-29 c水平降低。同时，褪黑激素显著下调lncRNA H19和上调miR-29 c水平。在我们的体外实验中，我们用高浓度葡萄糖培养基（33 mM）处理H9 c2细胞以模拟糖尿病状态。证实了miR-29 c的正调节和lncRNA H19以及丝裂原活化蛋白激酶（MAPK）途径的抑制明显减弱了高糖处理的H9 c2细胞中的凋亡。进行荧光素酶活性测定以评估miR-29 c在lncRNA H19和MAPK 13上的潜在靶位点。LncRNA H19沉默通过诱导miR-29 c表达显著下调miR-29 c靶基因MAPK 13的表达。最重要的是，我们的研究结果表明，褪黑激素通过抑制lncRNA H19/MAPK和增加miR-29 c水平来减轻细胞凋亡。我们的研究结果阐明了褪黑激素对糖尿病心肌细胞凋亡的一种新的保护机制，该机制涉及lncRNA H19/miR-29 c和MAPK通路的调节，为预防糖尿病患者DCM提供了一种有希望的策略。
Recent studies revealed that non-coding RNAs (ncRNAs) play a crucial role in pathophysiological processes involved in diabetic cardiomyopathy (DCM) that contribute to heart failure. The present study was designed to further investigate the anti-apoptotic effect of melatonin on cardiomyocytes in diabetic conditions, and to elucidate the potential mechanisms associated with ncRNAs. In animal models, we induced diabetes in SD rats by single intraperitoneal injection of streptozotocin (STZ) solution (55 mg/kg) at 18:00 in the evening, after a week of adaptive feeding. Our results indicate that melatonin notably alleviated cardiac dysfunction and cardiomyocyte apoptosis. In the pathological situation, lncRNA H19 level increased, along with a concomitant decrease in miR-29c level. Meanwhile, melatonin significantly downregulated lncRNA H19 and upregulated miR-29c levels. In our in vitro experiments, we treated H9c2 cells with high-concentration glucose medium (33 mM) to simulate the state of diabetes. It was verified that positive modulation of miR-29c and inhibition of lncRNA H19, as well as mitogen-activated protein kinase (MAPK) pathways, distinctly attenuated apoptosis in high-glucose-treated H9c2 cells. A luciferase activity assay was conducted to evaluate the potential target sites of miR-29c on lncRNA H19 and MAPK13. LncRNA H19 silencing significantly downregulated the expression of miR-29c target gene MAPK13 by inducing miR-29c expression. Most importantly, our results show that melatonin alleviated apoptosis by inhibiting lncRNA H19/MAPK and increasing miR-29c level. Our results elucidate a novel protective mechanism of melatonin on diabetic cardiomyocyte apoptosis, which involved the regulation of lncRNA H19/miR-29c and MAPK pathways, providing a promising strategy for preventing DCM in diabetic patients.
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