Translational Research最新文献_第5页

Predictive modeling of ARDS mortality integrating biomarker/cytokine, clinical and metabolomic data 整合生物标志物/细胞因子、临床和代谢组学数据的ARDS死亡率预测模型。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-24 DOI: 10.1016/j.trsl.2025.05.005

Ruslan Rafikov , Debrah M. Thompson , Olga Rafikova , Sara M. Camp , Roberto A. Ribas , Ramon C. Sun , Matthew S. Gentry , Nancy G. Casanova , Joe G N Garcia

Acute Respiratory Distress Syndrome (ARDS), characterized by the rapid onset of respiratory failure and mortality rates of ∼40%, remains a significant challenge in critical care medicine. Despite advances in supportive care, accurate prediction of ARDS mortality remains challenging, resulting in delayed delivery of targeted interventions and effective disease management. Traditional critical illness severity scores lack specificity for ARDS, underscoring the need for more precise prognostic tools for ARDS mortality. To address this crucial gap, we employed a multimodal approach to predict ARDS patients utilizing a comprehensive dataset comprised of integrated clinical, metabolomic, and biochemical/cytokine data from ARDS patients (collected within hours of ICU admission) to develop and validate predictive models of ARDS mortality risk. The most robust multimodal data model generated demonstrated superior predictive capability with an area under the curve (AUC) of 0.868 on the test set and 0.959 on the validation set. Notably, this model achieved perfect specificity in identifying non-survivors in the validation cohort, highlighting potential utility in guiding early and targeted interventions in ICU settings. Metabolomic analysis revealed significant alterations in crucial pathways associated with ARDS mortality with tryptophan metabolism, particularly the kynurenine pathway, emerging as the most significantly enriched metabolic route, as well as the NAD+ metabolism/nicotinamide phosphoribosyltransferase (NAMPT) and glycosaminoglycan biosynthesis pathways. These metabolic derangements were strongly confirmed by lipidomic/metabolomic analysis of lung tissues from a porcine sepsis/ARDS model. Together, these findings demonstrate the promise of integrating multimodal data to improve ARDS prognostication and to provide important insights into the complex metabolic derangements underlying severe ARDS. Identification of metabolic signatures, such as kynurenine and NAD+ metabolism/NAMPT pathways, may serve as a foundation for developing personalized and effective targeted interventions and management strategies for ARDS patients.

急性呼吸窘迫综合征（ARDS）的特点是呼吸衰竭发作迅速，死亡率约为40%，仍然是重症监护医学的一个重大挑战。尽管支持治疗取得了进展，但ARDS死亡率的准确预测仍然具有挑战性，导致有针对性的干预措施和有效的疾病管理延迟交付。传统的危重疾病严重程度评分对ARDS缺乏特异性，强调需要更精确的ARDS死亡率预后工具。为了解决这一关键的差距，我们采用了一种多模式方法来预测ARDS患者，利用由ARDS患者的综合临床、代谢组学和生化/细胞因子数据组成的综合数据集（在ICU入院数小时内收集）来建立和验证ARDS死亡率风险的预测模型。生成的最稳健的多模态数据模型显示出较好的预测能力，测试集的曲线下面积（AUC）为0.868，验证集的AUC为0.959。值得注意的是，该模型在识别验证队列中的非幸存者方面具有完美的特异性，突出了在ICU环境中指导早期和有针对性干预的潜在效用。代谢组学分析显示，与色氨酸代谢相关的关键途径，特别是犬尿氨酸途径，以及NAD+代谢/烟酰胺磷酸核糖基转移酶（NAMPT）和糖胺聚糖生物合成途径发生了显著变化。猪脓毒症/ARDS模型肺组织的脂质组学/代谢组学分析有力地证实了这些代谢紊乱。总之，这些发现表明，整合多模式数据有望改善ARDS预后，并为了解严重ARDS的复杂代谢紊乱提供重要见解。识别代谢特征，如犬尿氨酸和NAD+代谢/NAMPT途径，可能为制定针对ARDS患者的个性化和有效的靶向干预和管理策略奠定基础。

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引用次数: 0

sFRP5 ameliorates atherosclerosis by suppressing the JNK/TLR9 pathway in macrophages sFRP5通过抑制巨噬细胞的JNK/TLR9通路改善动脉粥样硬化。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-22 DOI: 10.1016/j.trsl.2025.05.004

Yue Yu , Han Chen , Rui Wang , Fei Xu, Jiasheng Yin, Tongtong Zang, Changyi Zhou, Chengpeng Liu, Chaofu Li, Li Shen, Junbo Ge

Secreted frizzled related protein 5 (sFRP5), an anti-inflammatory adipokine, plays a crucial role in various diseases, and its serum levels are low in patients with coronary artery disease (CAD). However, its role in atherosclerosis remains unclear. Therefore, we investigated the correlation between sFRP5 and plaque stability, along with the molecular mechanisms underlying atherosclerosis. In patients with CAD, serum sFRP5 levels were positively correlated with plaque stability, a predictor of thin-cap fibroatheromas (TCFAs). Recombinant sFRP5 (r-sFRP5) supplementation significantly increased plaque stability and ameliorated atherosclerosis progression in ApoE^-/- mice. Aortic RNA-sequencing (RNA-seq) revealed sFRP5-mediated regulation in inflammatory cells. Our experiments confirmed that sFRP5 inhibits inflammation and macrophage migration. Mechanistically, Toll-like receptor 9 (TLR9) was identified as a downstream target of sFRP5, and sFRP5 suppressed TLR9 expression by decreasing c-Jun N-terminal kinase (JNK) phosphorylation. These findings suggest that serum sFRP5 levels are associated with plaque stability and play a protective role in atherosclerosis by attenuating inflammation and macrophage infiltration via inhibition of the JNK/TLR9 pathway, thereby ameliorating the progression of atherosclerosis. This study highlights the potential of sFRP5 as both a biomarker and therapeutic target for plaque stability in atherosclerosis.

分泌性卷曲相关蛋白5 （sFRP5）是一种抗炎脂肪因子，在多种疾病中起着至关重要的作用，其在冠状动脉疾病（CAD）患者的血清水平较低。然而，其在动脉粥样硬化中的作用尚不清楚。因此，我们研究了sFRP5与斑块稳定性之间的关系，以及动脉粥样硬化的分子机制。在冠心病患者中，血清sFRP5水平与斑块稳定性呈正相关，斑块稳定性是薄帽纤维粥样硬化（TCFAs）的预测因子。重组sFRP5 （r-sFRP5）补充显著增加ApoE-/-小鼠斑块稳定性和改善动脉粥样硬化进展。主动脉rna测序（RNA-seq）显示sfrp5介导的炎症细胞调节。我们的实验证实了sFRP5抑制炎症和巨噬细胞迁移。在机制上，toll样受体9 （TLR9）被确定为sFRP5的下游靶点，sFRP5通过降低c-Jun n -末端激酶（JNK）磷酸化来抑制TLR9的表达。这些研究结果表明，血清sFRP5水平与斑块稳定性有关，并通过抑制JNK/TLR9通路减轻炎症和巨噬细胞浸润，从而改善动脉粥样硬化的进展，从而在动脉粥样硬化中发挥保护作用。这项研究强调了sFRP5作为动脉粥样硬化斑块稳定性的生物标志物和治疗靶点的潜力。

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引用次数: 0

Mechanism of adipose-derived stem cell-derived extracellular vesicles affecting macrophage efferocytosis by mediating ADAM17/MerTK in the apoptosis of tubular epithelial cells after sepsis-associated acute kidney injury 脓毒症相关急性肾损伤后，脂肪源性干细胞源性细胞外囊泡通过介导ADAM17/MerTK介导小管上皮细胞凋亡影响巨噬细胞efferocysis的机制

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-20 DOI: 10.1016/j.trsl.2025.05.002

Zhixiang Bian, Xiangxiang Wang, Xiaoxuan Su, Ming Yang, Rui Zhu, Shunjie Chen

Objective

This study explored the molecular mechanism of adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) improving post-sepsis-associated acute kidney injury (S-AKI) tubular epithelial cell (TEC) apoptosis by modulating ADAM17/MerTK-mediated macrophage efferocytosis.

Methods

The S-AKI mouse model was established by caecal ligation and puncture and intravenously injected with ADSC-EVs. Mouse kidney macrophages were cultured with LPS, cultured with EVs while transfecting with oe-ADAM17 or si-MerTK, then incubated with Jurkat cells. Mouse serum urea and creatinine, and KIM-1, efferocytosis- and apoptosis-related protein, inflammatory factor, cytokine, and soluble MerTK (sMerTK) levels were determined using colorimetric assay, immunohistochemistry, Western blot, and ELISA. Renal tubular injury, TEC apoptosis, macrophage efferocytosis, and M1/M2 polarization levels were assessed via HE staining, TUNEL staining, immunofluorescence, and flow cytometry, respectively. In vivo validation experiments were conducted.

Results

S-AKI mice displayed elevated levels of serum urea, creatinine, KIM-1, pro-inflammatory factors, pro-apoptotic proteins and ADAM17 protein, decreased anti-apoptotic protein and MerTK protein levels, and diminished M2 polarization. ADSC-EVs down-regulated ADAM17 and sMerTK, and increased cell membrane MerTK, macrophage recognition of apoptotic cells and efferocytosis, and M2 polarization in renal tissues of S-AKI mice and LPS-induced mouse renal macrophages, indicating that ADSC-EVs regulated ADAM17/MerTK-mediated macrophage efferocytosis and promoted M2 polarization. MerTK silencing partially reversed ADSC-EVs-regulated LPS-induced mouse renal macrophage efferocytosis and M2 polarization. In vivo, ADAM17 upregulation partly averted ADSC-EVs-regulated post-S-AKI TEC apoptosis in mouse renal tissues.

Conclusion

ADSC-EVs down-regulated sMerTK level and up-regulated macrophage membrane MerTK protein level by modulating ADAM17 to promote macrophage efferocytosis and ameliorate post-S-AKI TEC apoptosis and inflammation.

目的：探讨脂肪源性干细胞源性细胞外囊泡（ADSC-EVs）通过调节ADAM17/ mertk介导的巨噬细胞efferocytosis改善脓毒症后急性肾损伤（S-AKI）小管上皮细胞（TEC）凋亡的分子机制。方法：采用结扎法和穿刺法建立小鼠S-AKI模型，并静脉注射adsc - ev。小鼠肾巨噬细胞用LPS培养，用ev培养，同时转染oe-ADAM17或si-MerTK，然后与Jurkat细胞孵育。采用比色法、免疫组织化学、Western blot和ELISA检测小鼠血清尿素和肌酐、KIM-1、efferocytosis和凋亡相关蛋白、炎症因子、细胞因子和可溶性MerTK （sMerTK）水平。分别通过HE染色、TUNEL染色、免疫荧光和流式细胞术评估肾小管损伤、TEC凋亡、巨噬细胞efferocyte和M1/M2极化水平。进行了体内验证实验。结果：S-AKI小鼠血清尿素、肌酐、KIM-1、促炎因子、促凋亡蛋白和ADAM17蛋白水平升高，抗凋亡蛋白和MerTK蛋白水平降低，M2极化减弱。adsc - ev下调ADAM17和sMerTK，增加S-AKI小鼠肾组织和lps诱导的小鼠肾巨噬细胞细胞膜MerTK、巨噬细胞对凋亡细胞和efferocysis的识别以及M2极化，表明adsc - ev调节ADAM17/MerTK介导的巨噬细胞efferocysis，促进M2极化。MerTK沉默部分逆转了adsc - ev调节的lps诱导的小鼠肾巨噬细胞efferocysis和M2极化。在体内，ADAM17上调部分避免了adsc - ev调控的s- aki后小鼠肾组织TEC凋亡。结论：adsc - ev通过调节ADAM17下调巨噬细胞sMerTK水平，上调巨噬细胞膜MerTK蛋白水平，促进巨噬细胞effocysis，改善s - aki TEC后细胞凋亡和炎症。

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引用次数: 0

Modeling diabetic epitheliopathy using 3D-Organotypic corneal epithelium 利用3d器官型角膜上皮建立糖尿病上皮病变模型。

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-17 DOI: 10.1016/j.trsl.2025.05.003

Grazia Maugeri , Agata Grazia D’Amico , Salvatore Saccone , Francesca Bruno , Elisabetta Pricoco , Davide Scollo , Teresio Avitabile , Antonio Longo , Velia D’Agata

Diabetic keratopathy (DK) is a degenerative corneal disease occurring in more than 50 % of diabetic patients. DK is correlated with the hyperglycemic state causing morphological and functional changes in corneal layers. Currently, most studies on the cornea are performed on two-dimensional (2D) cultures in vitro or animal models. Although 2D culture models can provide large amounts of data at low cost, they poorly represent the complex pathophysiology of the human cornea and hardly predict in vivo responses that can be achieved with animal model studies. However, the use of the latter presents ethical problems. Therefore, it is necessary to identify new strategies and models that can integrate the information validly and effectively, to reduce the number of animals used. Here, we used human corneal epithelial cells (hCECs) derived from donor cornea differentiated into three-dimensional (3D)-organotypic air-liquid interface (ALI), which resemble the features of the corneal epithelium. The 3D-organotypic ALI corneal epithelium was subjected to high-glucose conditions to generate a model of diabetic epitheliopathy. Our model showed well-established molecular and cellular characteristics of this pathology, such as epithelial defects and inflammation, with increased expression of IL-1β, TNF-

α

, p-NF-kB, COX-2, MMP-2 and MMP-9. The data provided highlight the utility of 3D-organotypic corneal epithelium in modeling diabetic epitheliopathy, offering new avenues in drug screening, as well as in precision and personalized medicine.

糖尿病性角膜病变（DK）是一种退行性角膜疾病，发生在50%以上的糖尿病患者中。DK与高血糖状态引起的角膜层形态和功能改变有关。目前，大多数关于角膜的研究都是在体外二维培养或动物模型上进行的。尽管2D培养模型可以以低成本提供大量数据，但它们很难代表人类角膜复杂的病理生理，并且很难预测动物模型研究可以实现的体内反应。然而，后者的使用带来了伦理问题。因此，有必要确定新的策略和模型，可以有效地整合信息，以减少动物的使用数量。在这里，我们使用来自供体角膜的人角膜上皮细胞（hCECs）分化成三维(3D)-器官型气液界面（ALI），其特征与角膜上皮相似。将3d器官型ALI角膜上皮置于高糖条件下，生成糖尿病上皮病模型。我们的模型显示了这种病理的分子和细胞特征，如上皮缺陷和炎症，IL-1β、TNF-α、p-NF-kB、COX-2、MMP-2和MMP-9的表达增加。所提供的数据强调了3d器官型角膜上皮在糖尿病上皮病变建模中的效用，为药物筛选以及精确和个性化医疗提供了新的途径。

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引用次数: 0

Abundance of dopamine and its receptors in the brain and adipose tissue following diet-induced obesity or caloric restriction 饮食引起的肥胖或热量限制后大脑和脂肪组织中多巴胺及其受体的丰度

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-08 DOI: 10.1016/j.trsl.2025.05.001

Fleur W Hukema , Susanne Hetty , Christakis Kagios , Sofia Zelleroth , Giovanni Fanni , Maria J Pereira , Maria K Svensson , Magnus Sundbom , Anna Nilsson , Per E Andrén , Erika Roman , Jan W Eriksson

While obesity and type 2 diabetes (T2D) are associated with altered dopaminergic activity in the central nervous system and in adipose tissue (AT), the directions and underlying mechanisms remain inconclusive. Therefore, we characterized changes in the abundance of dopamine, its metabolites, and receptors DRD1 and DRD2 in the brain and AT upon dietary intervention or obesity. Male Wistar rats were fed either a standard pellet diet, a cafeteria diet inducing obesity and insulin resistance, or a calorie-restricted diet for 12 weeks. Abundance of dopamine and its receptors DRD1 and DRD2 were examined in brain regions relevant for feeding behavior and energy homeostasis. Furthermore, DRD1 and DRD2 protein levels were analyzed in rat inguinal and epidydimal AT and in human subcutaneous and omental AT from individuals with or without obesity. Rats with diet-induced obesity displayed higher dopamine levels, as well as DRD1 or DRD2 receptor levels in the caudate putamen and the nucleus accumbens core. Surprisingly, caloric restriction induced similar changes in DRD1 and DRD2, but not in dopamine levels, in the brain. Both diets reduced DRD1 abundance in inguinal and epidydimal AT, but upregulated DRD2 levels in inguinal AT. Furthermore, in human obesity, DRD1 protein levels were elevated only in omental AT, while DRD2 was upregulated in both omental and subcutaneous AT. These findings highlight dopaminergic responses to changes in energy balance, occurring both in the brain and AT. We propose that dopaminergic pathways are involved in tissue crosstalk during the development of obesity and T2D.

虽然肥胖和2型糖尿病（T2D）与中枢神经系统和脂肪组织（AT）中多巴胺能活性的改变有关，但其方向和潜在机制尚不明确。因此，我们表征了饮食干预或肥胖后大脑和AT中多巴胺、多巴胺代谢物以及受体DRD1和DRD2丰度的变化。雄性Wistar大鼠被喂食标准颗粒饮食、导致肥胖和胰岛素抵抗的自助餐厅饮食或限制卡路里饮食，为期12周。多巴胺及其受体DRD1和DRD2的丰度在与摄食行为和能量稳态相关的大脑区域被检测。此外，还分析了肥胖或非肥胖个体大鼠腹股沟和附睾AT以及人皮下和网膜AT中DRD1和DRD2蛋白水平。饮食诱导肥胖的大鼠显示出更高的多巴胺水平，以及尾状壳核和伏隔核核心的DRD1或DRD2受体水平。令人惊讶的是，热量限制引起了大脑中DRD1和DRD2的类似变化，但没有引起多巴胺水平的变化。两种饮食均降低了腹股沟和附睾AT中DRD1的丰度，但上调了腹股沟AT中DRD2的水平。此外，在人类肥胖中，DRD1蛋白水平仅在网膜AT中升高，而DRD2在网膜和皮下AT中均上调。这些发现强调了多巴胺能对能量平衡变化的反应，发生在大脑和AT中。我们认为多巴胺能通路在肥胖和T2D的发展过程中参与了组织串扰。

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Information for Readers 读者资讯

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-01 DOI: 10.1016/S1931-5244(25)00045-3

引用次数: 0

Editorial Advisory Board 编辑顾问委员会

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-01 DOI: 10.1016/S1931-5244(25)00043-X

引用次数: 0

Author Guidelines 作者指导方针

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-05-01 DOI: 10.1016/S1931-5244(25)00044-1

引用次数: 0

Cardioprotective effects of PARP Inhibitors: A meta-analysis of animal studies PARP抑制剂的心脏保护作用：动物研究的荟萃分析

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-04-30 DOI: 10.1016/j.trsl.2025.04.004

Seong Kyung Kim , Jae Hyun Kim , Inyeong Moon , Jiwon Min , Jieun Park , Myeong Gyu Kim

Poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitors are expected to provide benefits to the cardiovascular system. However, the cardioprotective effect of PARP inhibitors has not been systematically reviewed or quantitatively analyzed. This study aimed to assess the cardioprotective effects of PARP inhibitors through a meta-analysis of animal studies. Three databases PubMed, Web of Sciences, and Embase were searched until September 1, 2023. The risk of bias was assessed using SYRCLE’s Risk of Bias. A total of 74 animal studies that investigated the cardiac function of PARP inhibitors compared to placebo or vehicle, were included. Outcome measures were hemodynamic indexes, cardiac contractility, and biomarkers of myocardial injury. Pooled effect size was estimated using a random-effects model with RevMan 5.4. PARP inhibitors were associated with enhanced hemodynamic indexes, including cardiac output (standardized mean difference, 0.86 [95 % CI, 0.54 to 1.17]; p < 0.00001) and stroke volume (0.42 [0.07 to 0.76]; p = 0.02). PARP inhibitors were associated with increased cardiac contractility, including ejection fraction (0.71 [0.42 to 1.01]; p < 0.00001) and fractional shortening (0.96 [0.62 to 1.31]; p < 0.00001). PARP inhibitors were associated with decreased troponin І (-1.42 [-2.16 to -0.68]; p = 0.0002), plasma B-type natriuretic peptide (-0.95 [-1.56 to -0.33]; p = 0.003), creatine kinase (-1.81 [-2.63 to -0.99]; p < 0.0001), and infarct size (-1.58 [-2.01 to -1.14]; p < 0.00001). PARP inhibitors improve cardiac functions and attenuate myocardial injury in animals, which indicate the cardioprotective effects. Further human studies are necessary.

聚二磷酸腺苷[ADP]核糖)聚合酶（PARP）抑制剂有望为心血管系统提供益处。然而，PARP抑制剂的心脏保护作用尚未系统回顾或定量分析。本研究旨在通过动物研究的荟萃分析来评估PARP抑制剂的心脏保护作用。检索了PubMed、Web of Sciences和Embase三个数据库，直到2023年9月1日。偏倚风险采用sycle的偏倚风险评估。共纳入74项动物研究，研究了PARP抑制剂与安慰剂或对照剂的心功能。结果测量血液动力学指标、心脏收缩力和心肌损伤的生物标志物。使用RevMan 5.4的随机效应模型估计合并效应大小。PARP抑制剂与血流动力学指标增强相关，包括心输出量(标准化平均差，0.86 [95% CI， 0.54至1.17]；p & lt;0.00001)和行程体积(0.42 [0.07 ~ 0.76]；P = 0.02)。PARP抑制剂与心脏收缩力增加相关，包括射血分数(0.71 [0.42 ~ 1.01]；p & lt;0.00001)和分数缩短(0.96[0.62至1.31]；p & lt;0.00001)。PARP抑制剂与肌钙蛋白降低І相关(-1.42[-2.16至-0.68]；p = 0.0002)，血浆b型利钠肽(-0.95 [-1.56 ~ -0.33]；P = 0.003)，肌酸激酶(-1.81 [-2.63 ~ -0.99]；p & lt;0.0001)，梗死面积(-1.58[-2.01至-1.14]；p & lt;0.00001)。PARP抑制剂可改善动物心功能，减轻心肌损伤，表明其具有心脏保护作用。进一步的人体研究是必要的。

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引用次数: 0

tiRNA-HAR contributes to ischemic myocardial injury via facilitating HuR-mediated stability of p53 tiRNA-HAR通过促进hr介导的p53稳定性参与缺血性心肌损伤

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research

Pub Date : 2025-04-17 DOI: 10.1016/j.trsl.2025.04.002

Changhao Wang , Yuelin Gao , Kuiwu Liu , Yaozhi Zhang , Zhiyong Sun , Min Huang , Zhezhe Qu , Shuting Yu , Jiaqi Han , Zhongting Mei , Shunkang Dou , Jianhao Jiang , Ying Li , Na Li , Chuanhao Huang , Yuechao Dong , Baofeng Yang , Weijie Du

Cardiomyocyte death due to heart occlusion of coronary artery is the main driver to myocardial infarction (MI) and subsequent heart failure progression. tsRNA, a small RNA fragment from tRNA, has been shown to be implicated in many physiological and pathological processes by exerting different biological functions, but the roles of tsRNA in ischemic cardiac injury remain to be determined. The present study identified a hypoxia responsive-tiRNA (tiRNA-HAR) was markedly upregulated in ischemic mouse myocardium and hypoxic cardiomyocytes, respectively. Enforced expression of tiRNA-HAR by transfecting its mimic caused and aggravated, while knockdown of tiRNA-HAR mitigated cardiomyocyte apoptosis upon hypoxia. Cardiac specific knockdown of tiRNA-HAR mediated by AAV9 (adeno-associated virus 9) harboring an antisense oligonucleotide reduced cardiomyocytes apoptosis and improved cardiac function after MI. Mechanistically, tiRNA-HAR directly bound to HuR and enhanced the binding capacity of HuR and p53, thereby increasing the stability of p53. Silencing of HuR partially reversed the aggravative effects of tiRNA-HAR overexpression on cardiomyocyte apoptosis in the context of hypoxia. Collectively, our study reveals that tiRNA-HAR play a critical role in regulating cardiomyocytes apoptosis and cardiac injury via targeting HuR/p53 signaling axis after MI, and tiRNA-HAR might be a novel therapeutic target for treatment of ischemic heart disease.

冠状动脉心脏闭塞引起的心肌细胞死亡是心肌梗死（MI）和随后的心力衰竭进展的主要驱动因素。tsRNA是来自tRNA的一个小RNA片段，已被证明通过发挥不同的生物学功能参与许多生理和病理过程，但tsRNA在缺血性心脏损伤中的作用仍有待确定。本研究发现缺氧反应性的tirna （tiRNA-HAR）分别在缺血小鼠心肌和缺氧心肌细胞中显著上调。通过转染tiRNA-HAR模拟物，增强tiRNA-HAR的表达可引起并加重心肌细胞缺氧后的凋亡，而tiRNA-HAR的敲低可减轻心肌细胞缺氧后的凋亡。含有反义寡核苷酸的腺相关病毒9 （AAV9）介导的心脏特异性敲低tiRNA-HAR可减少心肌细胞凋亡，改善心肌功能。在机制上，tiRNA-HAR可直接与HuR结合，增强HuR与p53的结合能力，从而提高p53的稳定性。在缺氧环境下，HuR的沉默部分逆转了tiRNA-HAR过表达对心肌细胞凋亡的加重作用。综上所述，我们的研究表明，tiRNA-HAR在心肌梗死后通过靶向HuR/p53信号轴调控心肌细胞凋亡和心脏损伤中发挥了关键作用，tiRNA-HAR可能成为治疗缺血性心脏病的新靶点。

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引用次数: 0