PDF(Pubmed)
Abstract：
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus that can cause malignant arrhythmia and sudden death and is associated with cardiomyocyte dysfunction induced by hyperglycemia. Emerging evidence has revealed that transfer RNA-derived fragments (tRFs), a novel class of noncoding RNAs, play a crucial role in a variety of pathophysiologic processes, including cell death, cell growth and proliferation. However, it remains unknown whether and how tRFs are involved in cardiomyocyte dysfunction during the progression of DCM. In this study, we found that cardiomyocyte abnormalities were induced by high glucose (HG) treatment, as demonstrated by a decrease in cell viability and autophagy activation as well as an increase in cell death and proinflammatory cytokine release. Moreover, HG treatment resulted in differential expression of tRFs in cardiomyocytes, of which 4 upregulated and 1 downregulated tRFs were observed compared with the control group. The differential expression of 4 upregulated tRFs was primarily involved in cardiac dysfunction-related processes, such as autophagy, AGE-RAGE signaling pathway in diabetic complications, MAPK signaling pathway, insulin signaling pathway, FoxO signaling pathway, insulin resistance and peroxisome pathways based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, we found that tRF-5014a, the most significantly upregulated tRF among all tested tRFs, negatively regulated the expression of the autophagy-related protein ATG5. Importantly, inhibition of tRF-5014a not only abolished autophagy inactivation but also attenuated the decrease in cell viability and increase in cell death as well as proinflammatory cytokine release under HG conditions. These findings suggest that tRFs may contribute to HG-induced cardiomyocyte injury during DCM progression.
摘要：
糖尿病心肌病（DCM）是糖尿病的严重并发症，可引起恶性心律失常和猝死，并与高血糖引起的心肌细胞功能障碍有关。新的证据表明，转移RNA衍生片段(tRF)，一类新的非编码RNA，在各种病理生理过程中起着至关重要的作用，包括细胞死亡,细胞生长和增殖。然而,目前尚不清楚tRF是否以及如何参与DCM进展过程中的心肌细胞功能障碍。在这项研究中,我们发现心肌细胞异常是由高糖（HG）治疗引起的，如细胞活力和自噬激活降低以及细胞死亡和促炎细胞因子释放增加所证明的。此外，HG处理导致心肌细胞中tRFs的差异表达，与对照组相比，观察到4个上调和1个下调的tRF。4个上调的tRFs的差异表达主要参与心功能不全相关过程,比如自噬，AGE-RAGE信号通路在糖尿病并发症中的作用,MAPK信号通路,胰岛素信号通路,FoxO信号通路,基于京都基因和基因组百科全书（KEGG）途径富集分析的胰岛素抵抗和过氧化物酶体途径。此外，我们发现TRF-5014a,在所有测试的tRF中，最显著上调的tRF，负调控自噬相关蛋白ATG5的表达。重要的是,抑制tRF-5014a不仅消除了自噬失活，而且减轻了HG条件下细胞活力的降低和细胞死亡的增加以及促炎细胞因子的释放。这些发现表明，tRF可能有助于DCM进展过程中HG诱导的心肌细胞损伤。
