Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.
Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.
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DOI：
10.1016/j.yjmcc.2023.06.004
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发表时间：
2023-07
影响因子：
5
通讯作者：
Z. Meng;B. Liang;Yalin Wu;Caihong Liu;Han Wang;Yunhui Du;Lu Gan;E. Gao;W. Lau;T. Christ
中科院分区：
文献类型：
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作者：
Z. Meng;B. Liang;Yalin Wu;Caihong Liu;Han Wang;Yunhui Du;Lu Gan;E. Gao;W. Lau;T. Christ
糖尿病通过不完全理解的机制增强心肌缺血/再灌注（MI/R）损伤。脂联素（APN）是一种心脏保护性脂肪因子，在糖尿病中受到抑制。然而，低脂联素血症如何加重心脏损伤仍不完全清楚。miRNAs的失调在疾病发展中起着重要作用。然而，低脂联素血症是否改变心脏miRNA谱，导致糖尿病心脏injure.Methods和结果：野生型（WT）和APN敲除（APN-KO）小鼠进行MI/R。测定心脏microRNA谱。在MI/R后APN-KO小鼠中增加的23种miRNA中，miR-449 b的上调最显著（WT小鼠的3.98倍）。在WT小鼠中，施用miR-449 b模拟物增加了细胞凋亡，扩大了梗死面积，并损害了心脏功能。相反，在APN-KO小鼠中，anti-miR-449 b减少了细胞凋亡，减少了梗死面积，并改善了心脏功能。生物信息学分析预测了73个miR-449 b靶向基因，GO分析显示氧化应激是这些基因调控的主要途径。Venn分析和荧光素酶测定将Nrf-1和Ucp 3鉴定为两个最重要的miR-449 b靶标。在APN-KO小鼠中体内施用抗miR-449 b减弱MI/R刺激的超氧化物过度产生。体外实验表明，高糖高脂和模拟缺血再灌注可上调miR-449 b的表达，抑制Nrf-1和Ucp 3的表达。这些病理学效应通过抗miR-449 b或Nrf-1过表达而减弱。在验证我们在临床相关模型中的发现的最后尝试中，高脂饮食（HFD）诱导的糖尿病小鼠经受MI/R并用抗miR-449 b或APN治疗。糖尿病显著增加miR-449 b表达，下调Nrf-1和Ucp 3表达。抗miR-449 b或APN的管理保存心脏Nrf-1的表达，减少心脏氧化应激，减少细胞凋亡和梗死面积，并改善cardiac function.Conclusion：我们首次证明，低脂联素血症上调miR-449 b和抑制Nrf-1/Ucp 3的表达，促进氧化应激和加剧MI/R损伤在这个人群中。APN/miR-449 b/氧化应激通路的异常调节是糖尿病MI/R损伤的潜在治疗靶点。
Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear.Methods and Results:Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function.Conclusion:We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.