Role of microRNA-98 in Myocardial Ischemia Reperfusion Injury in Late Pregnancy

microRNA-98在妊娠晚期心肌缺血再灌注损伤中的作用

• 批准号: 10606041
• 负责人: Laila Aryan
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-06 至 2024-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606041
• 关键词: 3-Dimensional; Age; Apoptosis; Biological Assay; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Computer software; Data; Diabetes Mellitus; Diagnostic; Disease; Event; Female; Gene Expression; Heart; Heart Diseases; High Risk Woman; Hypertension; Hypoxia; In Vitro; Infarction; Inflammation; Injury; Late pregnancy; Lead; Life; Life Style; Luciferases; Maternal Age; Mediating; Micro Array Data; MicroRNAs; Microarray Analysis; Mitochondria; Modality; Modeling; Molecular; Mothers; Mus; Myocardial Infarction; Myocardial Reperfusion Injury; Obesity; Oxidative Stress; Pathologic Processes; Patients; Physiological Processes; Plasma; Predisposition; Pregnancy; Pregnant Women; Prevalence; Production; Prognosis; Rattus; Reactive Oxygen Species; Recording of previous events; Regulation; Regulator Genes; Relative Risks; Reperfusion Injury; Reperfusion Therapy; Reporting; Rodent; Role; STAT3 gene; Serum; Smoking; Societies; Stimulus; Testing; Therapeutic; Third Pregnancy Trimester; Western Blotting; Woman; advanced maternal age; age group; cardioprotection; cardiovascular disorder risk; circulating microRNA; early detection biomarkers; high risk; in vivo; inflammatory marker; innovation; knock-down; myocardial infarct sizing; novel; overexpression; peripartum cardiomyopathy; predictive tools; pregnant; prenatal; prognostic; protein expression; reproductive; therapeutic target; translational potential

Project Summary The prevalence of heart attack, also known as myocardial infarction (MI), in pregnancy has increased over the past decades due in part to rising maternal age and lifestyle changes. MI during late pregnancy carries a worse prognosis than in non-pregnant (NP) women for unclear reasons. The late-pregnant (LP) rodent is more prone to myocardial ischemia-reperfusion injury (IRI) compared to the NP rodent. Furthermore, reactive oxygen species (ROS) production in the heart is higher in LP mice subjected to IRI. However, the underlying molecular mechanisms involved in the higher susceptibility of late pregnancy to IRI are not clear. MicroRNAs (miRs) have emerged as a powerful novel regulator of gene expression. In the heart, several miRs have been involved in IRI, suggesting that regulation of their function could be used as a novel cardioprotective strategy. MicroRNA microarray analysis showed that the expression of microRNA-98-5p (miR98) was highly increased in the LP heart compared to the NP heart at baseline. Strikingly, miR98 was increased further in the LP heart compared to the NP heart when subjected to IRI. These miR98 expression dynamics may underlie the higher vulnerability and predisposition of the LP heart to IRI. miR98 is also significantly increased in the plasma of pregnant women at high risk of cardiovascular disease compared to healthy pregnant patients and healthy non-pregnant patients in the reproductive age. In vitro data shows that the expression of miR98 is increased in female cardiomyocytes subjected to hypoxia/reoxygenation, which mimics IRI. Knockdown of miR98 reduces apoptosis, ROS production, and inflammatory markers in female cardiomyocytes subjected to H/R. To investigate the mechanism of action of miR98, TargetScan software was used to predict miR98 targets. STAT3 and PGC-1α were strongly predicted as miR98 targets. STAT3 and PGC-1α are known negative regulators of reactive oxygen species production and their deletion in cardiomyocytes in vivo has been shown to predispose mice to peripartum cardiomyopathy. Expression of STAT3 and PGC-1α are lower in the LP rat hearts subjected to I/R injury compared to the NP rat hearts subjected to I/R injury. Furthermore, knockdown of miR98 in vitro increases STAT3 and PGC-1α protein expression, whereas miR98 overexpression reduces their expression, suggesting they could be targets of miR98. The hypotheses of this proposal are, i) induction of miR98 in LP leads to higher cardiac vulnerability to IRI via targeting STAT3 and PGC-1α, leading to increased cardiomyocyte death, ROS production, and inflammation, and ii) miR98 has the potential to be served as a therapeutic modality and as a biomarker for early prediction of cardiovascular disease in pregnancy.

项目摘要 心脏病发作的患病率，也被称为心肌梗死（MI），在怀孕期间增加了， 在过去几十年中，部分原因是产妇年龄的增加和生活方式的改变。妊娠晚期的MI会导致更严重的 预后比非妊娠（NP）妇女，原因不明。怀孕后期（LP）的啮齿动物更倾向于 心肌缺血再灌注损伤（IRI）相比，NP啮齿动物。此外，活性氧物质 (ROS)在经受IRI的LP小鼠中，心脏中的产量更高。然而，潜在的分子 晚期妊娠对IRI的易感性较高的机制尚不清楚。microRNAs（miRs） 成为一种强大的新型基因表达调节剂。在心脏中，几种miR参与了IRI， 提示调节它们的功能可用作新的心脏保护策略。microRNA 微阵列分析显示microRNA-98- 5 p（miR 98）在LP中的表达显著增加， 与基线时的NP心脏相比。值得注意的是，在LP心脏中miR 98进一步增加， 当受到IRI时，NP心脏。这些miR 98表达动态可能是更高的脆弱性的基础。 和LP心脏易患IRI的倾向。miR 98在孕妇血浆中也显著增加 与健康妊娠患者和健康非妊娠患者相比， 在生育年龄。体外数据显示，miR 98的表达在雌性心肌细胞中增加， 经受缺氧/复氧，其模拟IRI。miR 98的敲低减少细胞凋亡，ROS 生产，和炎症标志物在女性心肌细胞经受H/R。为了研究其机制 为了预测miR 98的作用，使用TargetScan软件来预测miR 98靶标。STAT 3和PGC-1α表达强烈， 作为miR 98的靶点。STAT 3和PGC-1α是已知的活性氧负调节因子 在体内心肌细胞中，它们的产生和缺失已显示使小鼠易患围产期疾病。 心肌病LP大鼠心肌I/R损伤后STAT 3和PGC-1α表达降低 与受到I/R损伤的NP大鼠心脏相比。此外，miR 98的体外敲低增加了 STAT 3和PGC-1α蛋白表达，而miR 98过表达降低其表达，提示 它们可能是miR 98的目标。该提议的假设是，i）在LP中诱导miR 98导致更高的 通过靶向STAT 3和PGC-1α，心脏对IRI的脆弱性增加，导致心肌细胞死亡，ROS ii）miR 98具有用作治疗方式和作为免疫调节剂的潜力。 妊娠期心血管疾病早期预测的生物标志物。