Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
复制标题
核 miR-320 通过激活脂肪酸代谢基因的转录引起心脏脂毒性来介导糖尿病引起的心脏功能障碍
DOI：
10.1161/circresaha.119.314898
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发表时间：
2019-12-06
影响因子：
20.1
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Li, Huaping;Fan, Jiahui;Wang, Dao Wen
基本原理：糖尿病常伴有心血管并发症，是糖尿病患者发病和死亡的主要原因，但糖尿病与心血管功能障碍的发生机制尚不清楚。目的：我们的目的是阐明高血糖引起的心功能不全的机制，糖尿病和导致心力衰竭的糖尿病并发症的db小鼠模型。方法和结果：我们首先通过微阵列和定量逆转录聚合酶链反应对db/db小鼠的microRNA（miRNAs）表达进行了分析，并鉴定了miR-125。320作为与疾病表型相关的关键miRNA。接下来，我们通过显示糖尿病患者衰竭心脏中相同miRNA的上调来确定这一发现的临床相关性。我们证明了miR-320在诱导糖尿病性心肌病中的因果作用，表明miR-320过表达加剧，而其抑制改善db/db小鼠的心脏表型。出乎意料的是，我们发现miR-320在转录水平上充当细胞核中的小激活RNA。通过染色质免疫沉淀测序和染色质免疫沉淀定量聚合酶链反应分析Ago 2（argonaute RISC催化组分2）和RNA聚合酶II响应于miR-320诱导，我们鉴定了CD 36（脂肪酸转位酶）作为该miRNA的关键靶基因，并显示诱导的CD 36表达是增加脂肪酸摄取的原因，从而引起心脏的脂毒性。结论：这些发现揭示了糖尿病引发的心功能障碍的新机制，提供了迄今为止仅在转染细胞中用合成RNA证明的小激活RNA的内源性情况，并提出了一种潜在的策略，以开发一种基于miRNA的治疗方法来治疗糖尿病相关的心血管并发症。
Rationale: Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among patients with diabetes mellitus, but little is known about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction.Objective: We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes mellitus and diabetic complications that lead to heart failure.Methods and Results: We first profiled the expression of microRNAs (miRNAs) by microarray and quantitative reverse transcription polymerase chain reaction on db/db mice and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the upregulation of the same miRNA in the failing heart of patients with diabetes mellitus. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA in the nucleus at the level of transcription. By chromatin immunoprecipitation sequencing and chromatin immunoprecipitation quantitive polymerase chain reaction analysis of Ago2 (argonaute RISC catalytic component 2) and RNA polymerase II in response to miR-320 induction, we identified CD36 (fatty acid translocase) as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart.Conclusions: These findings uncover a novel mechanism for diabetes mellitus-triggered cardiac dysfunction, provide an endogenous case for small activating RNA that has been demonstrated to date only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes mellitus-associated cardiovascular complications.