Nrf2 regulation of oxidative stress in heart failure and extra vesicular communication

项目摘要/摘要 尽管慢性心力衰竭(CHF)的治疗取得了进展，但它仍然是导致死亡和 世界范围内的发病率。Nrf2信号的减少与氧化应激密切相关 心脏重构和交感神经兴奋在心力衰竭发病机制中的作用。然而，有几个关键问题 我们目前对Nrf2信号调节失调和串扰分子机制的认识存在差距 在充血性心力衰竭患者的心脏和大脑之间。在这里，我们的长期目标是了解一种独特的机制，通过 在CHF中，NRF2信号通过器官内和器官间的通讯受到损害。在之前的研究中，我们展示了 MiRNAs和细胞外小泡(EVS)在CHF中Nrf2失调中的潜在作用。EV富集型 MiRNAs最近被认为是细胞间通讯和旁分泌信号的调节者。 在心血管系统的生理和病理过程中。这些发现导致了中央 心肌梗死(MI)诱导心脏优先分泌miRNA丰富的EV的假说 进入细胞外空间，在那里EV-miRNAs直接导致局部氧化应激增加 通过细胞间通讯，或通过破坏中枢神经系统而循环至中枢神经系统，引起交感兴奋 由于Nrf2信号的减少，氧化还原动态平衡。我们已经确定了几个针对Nrf2的miRNAs 在心肌细胞中选择性上调，并包含在EV中，分泌到 细胞外空间。我们还提供了心脏来源的EVS和Nrf2靶向miRNAs存在的证据 在大脑的交感神经调节区域。在这一强劲的初步数据的指导下，我们建议继续进行三项 具体目的：1)确定富含EV的miRNAs是否有助于Nrf2的翻译抑制和氧化还原 CHF状态下心脏细胞间通讯的失衡；2)确定心脏是否起源于 电动汽车参与器官间的交流，特别是心脏和大脑之间的相互对话 CHF的进展，以及3)确定来自CHF动物的循环EV是否转移了一种病理生理 大脑交感神经调节区的表型。这一目标也将评估EV介导的miRNA抑制物 给药(即对映体)通过抑制Nrf2和抗氧化剂的减少来减轻CHF的表型 酶信号。总体而言，拟议的研究具有创新性，因为它追求的是 富含miRNA的EV有助于增加局部水平和远程交感神经的氧化应激。 在充血性心力衰竭状态下，通过EV介导的通讯通过破坏氧化还原动态平衡调节大脑的区域。 这种新的通讯途径可能有助于解释心肌梗死后交感神经活动如何增加。 独立于经典神经通路的状态。将人体组织纳入这些研究将提供一种 独特的翻译成分，并可能导致新的治疗和干预慢性心力衰竭。

PROJECT SUMMARY/ABSTRACT Despite progress in the management of chronic heart failure (CHF), it remains a leading cause of mortality and morbidity worldwide. A reduction in Nrf2 signaling has been closely associated with oxidative stress-mediated cardiac remodeling and sympathetic excitation in the pathogenesis of CHF. However, there are several critical gaps in our current knowledge of the molecular mechanisms of Nrf2 signaling dysregulation and cross-talk between the heart and brain in CHF. Here our long-term goal is to understand a unique mechanism by which Nrf2 signaling is impaired through intra- and inter-organ communication in CHF. In previous studies we showed the potential involvement of miRNAs and extracellular vesicles (EVs) in Nrf2 dysregulation in CHF. EV-enriched miRNAs have recently emerged as regulators of intercellular communication and paracrine signaling mediators during physiological and pathological processes in the cardiovascular system. These findings led to the central hypothesis that myocardial infarction (MI) induces the preferential secretion of miRNA-enriched EVs from cardiac cells into the extracellular space where EV-miRNAs either directly contribute to increased local oxidative stress via intercellular communication, or circulate to the CNS evoking sympathetic excitation by disrupting central redox homeostasis due to a reduction in Nrf2 signaling. We have identified several miRNAs that target Nrf2 mRNA and are selectively upregulated in cardiac cells and contained in EVs that are secreted into the extracellular space. We also provide evidence that cardiac-derived EVs and Nrf2-targeting miRNAs are present in sympatho-regulatory areas of the brain. Guided by this strong preliminary data, we propose to pursue three Specific Aims: 1) To determine if EV-enriched miRNAs contribute to Nrf2 translational inhibition and redox imbalance through intercellular communication in the heart in the CHF state; 2) To determine if cardiac derived EVs participate in inter-organ communication, especially cross-talk between the heart and brain in the progression of CHF, and 3) To determine if circulating EVs from CHF animals transfer a pathophysiological phenotype in sympatho-regulatory areas of the brain. This aim will also evaluate if EV-mediated miRNA inhibitor delivery (i.e. antagomirs) attenuates the CHF phenotype by inhibition of the decrease in Nrf2 and antioxidant enzyme signaling. Collectively, the proposed research is innovative because it pursues the novel idea that miRNA-enriched EVs contribute to increased oxidative stress at the local level and in remote sympatho- regulatory areas of the brain via EV-mediated communication by disrupting redox homeostasis in the CHF state. This novel communication pathway may help to explain how sympathetic nerve activity increases in the post MI state independent of classical neural pathways. Incorporation of human tissue into these studies will provide a unique translational component and potentially lead to new therapies and interventions in CHF.