microRNA Regulation of The Cocaine Effects on the Cardiovascular System

microRNA 调节可卡因对心血管系统的影响

基本信息

  • 批准号:
    10016586
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-10-01 至 2024-09-30
  • 项目状态:
    已结题

项目摘要

Despite the opioid overdose crisis, cocaine remains a widely abused illicit drug by the public and by veterans. While opioid overdose primarily causes respiratory failure, cocaine abuse is mainly associated with cardiovascular (CV) toxicities, which include hypertension (HTN), aortic stiffness, and atherosclerosis. Indeed, cocaine abuse represents a significant CV risk for the general population and for veterans. It is known that cocaine stimulates the sympathetic nervous system (SNS) by inhibiting norepinephrine (NE) reuptake at nerve terminals; however, recent evidence suggests that inhibition of NE reuptake may not be the major driver of cocaine-induced HTN. As such, the mechanisms mediating the effects of cocaine on the CV system remain largely unknown. To that end, we recently performed small RNA and RNA sequencing in the aortas from mice treated with cocaine, cocaine methiodide (CM, which does not enter the central nervous system), or saline to identify potential microRNA (miR)—mRNA pathways that mediate the CV effects of cocaine. Nine miR—mRNA pathways were implicated. We prioritized and identified two miR- mRNA axes based on their levels of expression changes and relevance to CV physiology. They are: 1) the ↑miR-30c—↓Malic Enzyme 1 (ME1)—↑reactive oxygen species (ROS) activity, which is crucial in HTN and vascular aging (aortic stiffness); and 2) the ↓miR-423—↑Cacna2d2 (encoding the α2δ-2 subunit of voltage-dependent calcium channels) —↑calcium influx resulting in increased intracellular calcium concentration ([Ca2+]i) which is critical in controlling vascular smooth muscle cell (SMC) contractility and blood pressure (BP). We thoroughly investigated the miR-30c pathway and recently published our findings in the journal Hypertension. In preliminary studies, we showed that cocaine- and CM-induced silencing of miR-423-5p expression and subsequent upregulation of Cacna2d2 led to increased [Ca2+]i, which augmented contractility in cultured SMCs. Furthermore, miR-423-5p overexpression ameliorated cocaine-induced BP elevation in vivo. Interestingly, miR-423-5p has been associated with heart failure and coronary artery disease. Its role in the pathogenesis of HTN remains unknown. Based on our published work and preliminary studies, we hypothesize that the miR-423—Cacna2d2 axis plays an important role in cocaine-induced HTN by regulating calcium influx and intracellular calcium concentrations ([Ca2+]i) in vascular cells. In addition, recent studies support a strong crosstalk between these two biological processes—Ca2+ signaling and ROS. We have pilot data showing that modification of both miR axes largely abrogated cocaine-induced SMC contraction. Therefore, we further hypothesize that these two pathways work synergistically to mediate cocaine-induced CV consequences. We will thoroughly characterize the ↓miR-423-5p— ↑Cacna2d2—↑ [Ca2+]i axis and its interaction with the ↑miR-30c—↓ME1—↑ROS pathway in mediating the effects of cocaine on the CV system by using complimentary and vertically integrated in vitro, ex vivo, and in vivo models. In addition, we will measure NE and its metabolite levels, as well as use Prazosin (an -blocker) to block the effects of NE in the in vivo experiments, aiming to characterize the potential interplay between the miR-mRNA axes and SNS in mediating the CV effects of cocaine.
尽管出现了阿片类药物过量危机,但可卡因仍然是一种被公众广泛滥用的非法药物 由退伍军人提供。虽然阿片类药物过量主要导致呼吸衰竭,但可卡因滥用主要是 与心血管(CV)毒性有关,包括高血压(HTN)、主动脉僵硬、 和动脉粥样硬化。事实上,滥用可卡因对一般人来说是一种重大的个人简历风险。 人口和退伍军人。众所周知,可卡因刺激交感神经系统 (SNS)通过抑制神经末梢的去甲肾上腺素(NE)重摄取;然而,最近的证据 提示NE再摄取抑制可能不是可卡因诱发HTN的主要驱动因素。AS 如此一来,可卡因对心血管系统产生影响的机制仍然很大程度上是未知的。 为此,我们最近在小鼠的动脉中进行了小RNA和RNA测序 用可卡因、甲碘可卡因(CM,不进入中枢神经系统)治疗, 或生理盐水,以确定潜在的microRNA(MiR)-mRNA通路,介导心血管效应 可卡因。共涉及9条miR-mRNA通路。我们确定并确定了两个MIR- MRNA轴基于其表达水平的变化以及与心血管生理学的相关性。他们 1)↑miR-30c-↓苹果酸酶1(ME1)-↑活性氧物种(ROS)活性, 在HTN和血管老化(主动脉僵硬)中起关键作用;和2)↓miR-423-↑Cacna 2d2 (编码电压依赖性钙通道的α2δ-2亚单位)-↑钙内流 增加细胞内钙离子浓度([Ca~(2+)]i),这是控制血管的关键 平滑肌细胞(SMC)的收缩能力和血压(BP)。我们彻底调查了 最近在《高血压》杂志上发表了我们的研究结果。在预赛中 研究表明,可卡因和CM诱导miR-423-5p表达沉默和 随后Cacna 2d2的上调导致[Ca~(2+)]i升高,从而增强了血管的收缩能力 培养的SMC。此外,miR-423-5p过表达可改善可卡因诱发的血压 活体内抬高。有趣的是,miR-423-5p与心力衰竭和冠状动脉病变有关 动脉疾病。其在HTN发病机制中的作用尚不清楚。基于我们发布的 工作和初步研究,我们假设miR-423-Cacna2d2轴起作用 钙离子内流和细胞内调节在可卡因诱发HTN中的重要作用 血管细胞内钙浓度([Ca~(2+)]i)。此外,最近的研究支持了一个强有力的 这两个生物过程之间的串扰-钙信号和ROS。我们有试点数据 结果表明,两个miR轴的改变在很大程度上取消了可卡因引起的SMC收缩。 因此,我们进一步假设,这两条途径协同工作,以中介 可卡因引起的脑血管意外后果。我们将彻底表征↓MIR-423-5P- ↑CaNa2d2-↑[Ca~(2+)]i轴及其与↑miR-30c-↓ME1-↑ROS通路的相互作用 用互补性和垂直性调节可卡因对CV系统的影响 集成了体外、体外和体内模型。此外,我们还将测定去甲肾上腺素及其代谢产物 在活体实验中,以及使用哌唑嗪(一种阻滞剂)来阻断NE的影响, 目的研究miR-mRNA轴与SNS之间的相互作用。 可卡因的心血管效应。

项目成果

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{{ truncateString('CHUNMING DONG', 18)}}的其他基金

The role of extracellular vesicle-associated MicroRNAs in HIV-associated atherosclerosis
细胞外囊泡相关 MicroRNA 在 HIV 相关动脉粥样硬化中的作用
  • 批准号:
    10619831
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
microRNA Regulation of The Cocaine Effects on the Cardiovascular System
microRNA 调节可卡因对心血管系统的影响
  • 批准号:
    10514596
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
microRNA Regulation of The Cocaine Effects on the Cardiovascular System
microRNA 调节可卡因对心血管系统的影响
  • 批准号:
    10293591
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
MicroRNA Regulation of Endothelial Progenitor Senescence in HIV Infection
HIV 感染中内皮祖细胞衰老的 MicroRNA 调控
  • 批准号:
    8847025
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
MicroRNAs as Determinants of Endothelial Progenitor Cell Senescence
MicroRNA 作为内皮祖细胞衰老的决定因素
  • 批准号:
    8663151
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
MicroRNAs as Determinants of Endothelial Progenitor Cell Senescence
MicroRNA 作为内皮祖细胞衰老的决定因素
  • 批准号:
    8440279
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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