Publications by authors named "Jean C Bopassa"

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy.

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Mitochondrial inner membrane protein (Mitofilin/Mic60) is part of a big complex that constituent the mitochondrial inner membrane organizing system (MINOS), which plays a critical role in maintaining mitochondrial architecture and function. We recently showed that Mitofilin physically binds to Cyclophilin D, and disruption of this interaction promotes the opening of mitochondrial permeability transition pore (mPTP) and determines the extent of I/R injury. Here, we investigated whether Mitofilin knockout in the mouse enhances myocardial injury and inflammation after I/R injury.

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The receptor-interacting protein kinase 3 (RIP3) has been reported to regulate programmed necrosis-necroptosis forms of cell death with important functions in inflammation. We investigated whether RIP3 translocates into mitochondria in response to renal ischemia-reperfusion (I/R) to interact with inner mitochondrial protein (Mitofilin) and promote mtDNA release into the cytosol. We found that release of mtDNA activates the cGAS-STING pathway, leading to increased nuclear transcription of pro-inflammatory markers that exacerbate renal I/R injury.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder with no known cure. PD is characterized by locomotion deficits, nigrostriatal dopaminergic neuronal loss, mitochondrial dysfunctions and formation of α-Synuclein aggregates. A well-conserved and less understood family of Tubulin Polymerization Promoting Proteins (TPPP) is also implicated in PD and related disorders, where TPPP exists in pathological aggregates in neurons in patient brains.

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Recently we showed that homoarginine supplementation confers kidney protection in diabetic mouse models. In this study we tested whether the protective effect of homoarginine is nitric oxide synthase-3 (NOS3)-independent in diabetic nephropathy (DN). Experiments were conducted in NOS3 deficient (NOS3 ) mice and their wild type littermate using multiple low doses of vehicle or streptozotocin and treated with homoarginine via drinking water for 24 weeks.

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Mitochondrial dysfunction plays a critical role in the pathophysiology of Parkinson's disease (PD). The inner mitochondrial membrane (IMM) protein, Mitofilin or Mic60, has been shown to play a key role in controlling and maintaining mitochondrial cristae morphology, and its dysregulation induces cyto-deleterious effects. Here, we investigated the mechanism underlying Mitofilin degradation in dopaminergic neuron death using N27-A cells, and Human Dopamine Neuronal Primary cells treated with PD stressors, Dopamine (DA) or Rotenone (Rot).

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Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion induces cardioprotective effects against I/R injury activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts.

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MPV17 is an inner mitochondrial membrane protein whose mutation results in mitochondrial DNA (mtDNA) depletion diseases such as neurohepatopathy. MPV17 is expressed in several organs including the liver and kidneys. Here, we investigated its role and mechanism of action in cardiac ischemia/reperfusion (I/R) injury.

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Mitochondrial inner membrane protein (Mitofilin or Mic60) is a mitochondria-shaping protein that plays a key role in maintaining mitochondrial cristae structure and remodeling. We recently showed that Mitofilin knockdown in H9c2 myoblasts induces mitochondrial structural damage resulting in mitochondrial dysfunction that is responsible for cell death via apoptosis. Here, we investigated the role of Mitofilin regulation in ischemia/reperfusion (I/R) injury and studied the relationship between Mitofilin and Cyclophilin (CypD), a key regulator of mitochondrial permeability transition pore (mPTP) opening.

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Ferroptosis is a distinct iron-dependent mechanism of regulated cell death recognized in cancer and ischemia/reperfusion (I/R) injury of different organs. It has been reported that molecules such as liproxstatin-1 (Lip-1) inhibit ferroptosis and promote cell survival however, the mechanisms underlying this action are not clearly understood. We investigated the role and mechanism of Lip-1 in reducing cell death in the ischemic myocardium.

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Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury.

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Background: Recently, we showed that exogenous treatment with estrogen (E2) rescues pre-existing advanced heart failure (HF) in mice. Since most of the biological actions of E2 are mediated through the classical estrogen receptors alpha (ERα) and/or beta (ERβ), and both these receptors are present in the heart, we examined the role of ERα and ERβ in the rescue action of E2 against HF.

Methods: Severe HF was induced in male mice by transverse aortic constriction-induced pressure overload.

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The identification of the mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane shed light on the intricate components necessary for mitochondria to form their signature cristae in which many protein complexes including the electron transport chain are localized. Mic60/mitofilin has been described as the core component for the assembly and maintenance of MICOS, thus controlling cristae morphology, protein transport, mitochondrial DNA transcription, as well as connecting the inner and outer mitochondrial membranes. Although Mic60 homologs are present in many species, mammalian Mic60 is only recently gaining attention as a critical player in several organ systems and diseases with mitochondrial-defect origins.

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Mitofilin is an inner membrane protein that has been defined as a mitochondria-shaping protein in controlling and maintaining mitochondrial cristae structure and remodeling. We determined the role of mitofilin in cell survival by investigating the mechanism underlying mitofilin knockdown-induced cell death by apoptosis. Cultured H9c2 myoblasts and HEK 293 cells were treated with mitofilin siRNA or scrambled siRNA for 24 h.

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Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described.

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Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of that was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate's secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeating motif, causing the compound to adopt a unique right-handed 3 helical structure.

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Background And Purpose: Recent evidence indicates that GPER (G protein-coupled oestrogen receptor 1) mediates acute pre-ischaemic oestrogen-induced protection of the myocardium from ischaemia/reperfusion injury via a signalling cascade that includes PKC translocation, ERK1/2/ GSK-3β phosphorylation and inhibition of the mitochondrial permeability transition pore (mPTP) opening. Here, we investigated the impact and mechanism involved in post-ischaemic GPER activation in ischaemia/reperfusion injury. We determined whether GPER activation at the onset of reperfusion confers cardioprotective effects by protecting against mitochondrial impairment and mitophagy.

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Reactive oxygen species (ROS) generation has been implicated in many pathologies including ischemia/reperfusion (I/R) injury. This led to multiple studies on antioxidant therapies to treat cardiovascular diseases but paradoxically, results have so far been mixed as ROS production can be beneficial as a signaling mechanism and in cardiac protection via preconditioning interventions. We investigated whether the differential impact of increased ROS in injury as well as in protection could be explained by their site of production on the mitochondrial electron transport chain.

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Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice.

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Background: Estrogen pretreatment has been shown to attenuate the development of heart hypertrophy, but it is not known whether estrogen could also rescue heart failure (HF). Furthermore, the heart has all the machinery to locally biosynthesize estrogen via aromatase, but the role of local cardiac estrogen synthesis in HF has not yet been studied. Here we hypothesized that cardiac estrogen is reduced in HF and examined whether exogenous estrogen therapy can rescue HF.

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Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively.

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There is discrepancy regarding the duration of reperfusion required using 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) staining to assess myocardial infarction in an isolated, perfused heart model. Several investigators prefer long-term reperfusion (120 minutes) to determine myocardial injury, while others have used a shorter duration (30-40 minutes). We investigated whether oxygen surrounding the myocardium during ischemia plays a critical role in the installation of myocardial infarction during reperfusion.

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The large-conductance Ca(2+)- and voltage-activated K(+) channel (BK(Ca), MaxiK), which is encoded by the Kcnma1 gene, is generally expressed at the plasma membrane of excitable and nonexcitable cells. However, in adult cardiomyocytes, a BK(Ca)-like channel activity has been reported in the mitochondria but not at the plasma membrane. The putative opening of this channel with the BK(Ca) agonist, NS1619, protects the heart from ischemic insult.

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The heart is an organ that requires an important energy input to ensure its contractile function. Myocardial ischemia happens when there is a deficiency of blood flow that is responsible for the passage from an aerobic to anaerobic metabolism. Myocardial ischemia results from an imbalance between inputs and the needs of nutrient and oxygen to the myocardium.

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