Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse?

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function.

Engineered Extracellular Vesicles: Emerging Therapeutic Strategies for Translational Applications.

Extracellular vesicles (EVs) are small, membrane-bound vesicles used by cells to deliver biological cargo such as proteins, mRNA, and other biomolecules from one cell to another, thus inducing a specific response in the target cell and are a powerful method of cell to cell and organ to organ communication, especially during the pathogenesis of human disease. Thus, EVs may be utilized as prognostic and diagnostic biomarkers, but they also hold therapeutic potential just as mesenchymal stem cells have been used in therapeutics. However, unmodified EVs exhibit poor targeting efficacy, leading to the necessity of engineered EVS.

Extracellular Vesicle MicroRNAs in Heart Failure: Pathophysiological Mediators and Therapeutic Targets.

Extracellular vesicles (EVs) are emerging mediators of intracellular and inter-organ communications in cardiovascular diseases (CVDs), especially in the pathogenesis of heart failure through the transference of EV-containing bioactive substances. microRNAs (miRNAs) are contained in EV cargo and are involved in the progression of heart failure. Over the past several years, a growing body of evidence has suggested that the biogenesis of miRNAs and EVs is tightly regulated, and the sorting of miRNAs into EVs is highly selective and tightly controlled.

Extracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart Failure.

Background: Chronic heart failure (CHF) is associated with redox imbalance. Downregulation of Nrf2 (nuclear factor [erythroid-derived 2]-like 2) plays important roles in disrupting myocardial redox homeostasis and mediating sympathetic nerve activity in the setting of CHF. However, it is unclear if circulating extracellular vesicles (EVs) elicit sympathetic excitation in CHF by disrupting central redox homeostasis.

Skeletal Muscle Nrf2 Contributes to Exercise-Evoked Systemic Antioxidant Defense Via Extracellular Vesicular Communication.

This review explores the hypothesis that the repetitive contraction-relaxation that occurs during chronic exercise activates skeletal myocyte nuclear factor erythroid-derived 2-like 2 (Nrf2) to upregulate antioxidant enzymes. These proteins are secreted into the circulation within extracellular vesicles and taken up by remote cells, thus providing remote organs with cytoprotection against subsequent oxidative stress.

Regulation of Nrf2 signaling pathway in heart failure: Role of extracellular vesicles and non-coding RNAs.

The balance between pro- and antioxidant molecules has been established as an important driving force in the pathogenesis of cardiovascular disease. Chronic heart failure is associated with oxidative stress in the myocardium and globally. Redox balance in the heart and brain is controlled, in part, by antioxidant proteins regulated by the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which is reduced in the heart failure state.

Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia.

MicroRNA-124 (miR-124), a brain-enriched microRNA, is known to regulate microglial quiescence. Psychostimulants such as cocaine have been shown to activate microglia by downregulating miR-124, leading, in turn, to neuroinflammation. We thus rationalized that restoring the levels of miR-124 could function as a potential therapeutic approach for cocaine-mediated neuroinflammation.

Spatial multi-scaled chimera states of cerebral cortex network and its inherent structure-dynamics relationship in human brain.

Human cerebral cortex displays various dynamics patterns under different states, however the mechanism how such diverse patterns can be supported by the underlying brain network is still not well understood. Human brain has a unique network structure with different regions of interesting to perform cognitive tasks. Using coupled neural mass oscillators on human cortical network and paying attention to both global and local regions, we observe a new feature of chimera states with multiple spatial scales and a positive correlation between the synchronization preference of local region and the degree of symmetry of the connectivity of the region in the network.

Extracellular vesicular MicroRNA-27a* contributes to cardiac hypertrophy in chronic heart failure.

Under stress, the heart undergoes extensive remodeling resulting in cardiac fibrosis and hypertrophy, ultimately contributing to chronic heart failure (CHF). Alterations in microRNA levels are associated with dysfunctional gene expression profiles involved in the pathogenesis of heart failure. We previously showed that myocardial infarction-induced microRNA-enriched extracellular vesicles (EVs) contribute to the reduction in antioxidant enzymes by targeting Nrf2 signaling in CHF.

Therapeutic Effects of Nrf2 Activation by Bardoxolone Methyl in Chronic Heart Failure.

Oxidative stress plays an important role in the pathogenesis of chronic heart failure (CHF) in many tissues. Increasing evidence suggests that systemic activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling can protect against postinfarct cardiac remodeling by reducing oxidative stress. However, it remains to be elucidated if Nrf2 activation exerts therapeutic effects in the CHF state.

A two-layered brain network model and its chimera state.

Based on the data of cerebral cortex, we present a two-layered brain network model of coupled neurons where the two layers represent the left and right hemispheres of cerebral cortex, respectively, and the links between the two layers represent the inter-couplings through the corpus callosum. By this model we show that abundant patterns of synchronization can be observed, especially the chimera state, depending on the parameters of system such as the coupling strengths and coupling phase. Further, we extend the model to a more general two-layered network to better understand the mechanism of the observed patterns, where each hemisphere of cerebral cortex is replaced by a highly clustered subnetwork.

Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial Proliferation in Mice.

Long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs), play an important regulatory role in controlling various biological processes. Both in vitro and in vivo studies have demonstrated that lincRNA-Cox2 plays a global regulatory role in regulating the expression of immune genes. Extracellular vesicles (EVs) are cell-derived nanosized membrane vesicles that have gained increasing attention in recent years due to their ability to efficiently deliver therapeutics to specific target organs or cell types.

Direct and selective lineage conversion of human fibroblasts to dopaminergic precursors.

Transplantation of dopaminergic precursors (DPs) is a promising therapeutic strategy of Parkinson's disease (PD). However, limited cell source for dopaminergic precursors has become a major obstacle for transplantation therapy. Our group demonstrated previously that mouse fibroblasts can be reprogrammed into induced dopaminergic precursors (iDPs) with high differentiation efficiency.

Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal-regulated kinase pathways.

Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes.

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons.

Background: Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases. Due to the ethical concerns of ESCs-derived neural progenitor cells (NPCs) and tumorigenic potential of iPSCs, reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.

Methods: Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors (TFs) Foxg1, Sox2, and Brn2.

Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration.

Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor κB (NF-κB) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation.

Influence of stochastic perturbations on the cluster explosive synchronization of second-order Kuramoto oscillators on networks.

Explosive synchronization in networked second-order Kuramoto oscillators has been well studied recently and it is revealed that the synchronization process is featured by cluster explosive synchronization. However, little attention has been paid to the influence of noise or perturbation. We here study this problem and discuss the influences of noise and perturbation.

Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure.

The imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems results in macromolecular damage and disruption of cellular redox signaling, affecting cardiac structure and function, thus contributing to contractile dysfunction, myocardial hypertrophy, and fibrosis in chronic heart failure [chronic heart failure (CHF)]. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is an important antioxidant defense mechanism and is closely associated with oxidative stress-mediated cardiac remodeling in CHF. In the present study, we investigated the regulation of myocardial Nrf2 in the postmyocardial infarction (post-MI) state.

Asymmetric couplings enhance the transition from chimera state to synchronization.

Chimera state has been well studied recently, but little attention has been paid to its transition to synchronization. We study this topic here by considering two groups of adaptively coupled Kuramoto oscillators. By searching the final states of different initial conditions, we find that the system can easily show a chimera state with robustness to initial conditions, in contrast to the sensitive dependence of chimera state on initial conditions in previous studies.

Serial deletion reveals structural basis and stability for the core enzyme activity of human glutaminase 1 isoforms: relevance to excitotoxic neurodegeneration.

Background: Glutaminase 1 is a phosphate-activated metabolic enzyme that catalyzes the first step of glutaminolysis, which converts glutamine into glutamate. Glutamate is the major neurotransmitter of excitatory synapses, executing important physiological functions in the central nervous system. There are two isoforms of glutaminase 1, KGA and GAC, both of which are generated through alternative splicing from the same gene.

A small change in neuronal network topology can induce explosive synchronization transition and activity propagation in the entire network.

We here study explosive synchronization transitions and network activity propagation in networks of coupled neurons to provide a new understanding of the relationship between network topology and explosive dynamical transitions as in epileptic seizures and their propagations in the brain. We model local network motifs and configurations of coupled neurons and analyze the activity propagations between a group of active neurons to their inactive neuron neighbors in a variety of network configurations. We find that neuronal activity propagation is limited to local regions when network is highly clustered with modular structures as in the normal brain networks.

Influence of brain-derived neurotrophic factor-tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure.

Key Points: Impairment of baroreflex function is associated with the progression of chronic heart failure (CHF) and a poor prognosis. The baroreflex desensitization in CHF is at least partly the result of central neuronal network dysfunction. The dorsal medial nucleus tractus solitarius (dmNTS) has long been appreciated as a primary site of baroreceptor afferent termination in the central nervous system.

BDNF contributes to angiotensin II-mediated reductions in peak voltage-gated K+ current in cultured CATH.a cells.

Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II.