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1.
Cell Death Differ ; 25(9): 1671-1685, 2018 09.
Article in English | MEDLINE | ID: mdl-29459772

ABSTRACT

Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk. In vivo, streptozotocin administration to mice induced oxidative changes and ER stress in the heart, events that were abolished by pargyline. Moreover, MAO inhibition prevented both mast cell degranulation and altered collagen deposition, thereby normalizing diastolic function. Taken together, these results elucidate the mechanisms underlying MAO-induced damage in diabetic cardiomyopathy and provide novel evidence for the role of MAOs in inflammation and inter-organelle communication. MAO inhibitors may be considered as a therapeutic option for diabetic complications as well as for other disorders in which mast cell degranulation is a dominant phenomenon.


Subject(s)
Cell Degranulation/drug effects , Endoplasmic Reticulum Stress , Mitochondria/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Ventricular Remodeling/drug effects , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/pathology , Endoplasmic Reticulum Stress/drug effects , Glucose/pharmacology , Interleukin-1beta/pharmacology , Male , Mice , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Monoamine Oxidase/chemistry , Monoamine Oxidase/genetics , Muscle Cells/cytology , Muscle Cells/metabolism , Muscle Cells/physiology , Myocardium/metabolism , Myocardium/pathology , RNA Interference , RNA, Small Interfering/metabolism , Rats , Reactive Oxygen Species/metabolism
2.
J Neuroimmunol ; 318: 15-20, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29395321

ABSTRACT

Despite growing evidence that cytokines and chemokines are expressed in humans and rats after heat stress, the cellular mechanisms underlying the effects on the brain after heatstroke (HS) are not fully understood. In this study, we observed time course changes of chemokines in rat brain tissues and elucidated what kinds of cortical cells were affected after HS. Male SD rats were anesthetized and randomly separated into two groups as follows: (a) normothermic sham and (b) HS rats. Rats were sacrificed at different time points (0, 1, 3, 6, and 12h after heat exposure, n=5 in each group) to the end of the experiment in order to extract the mRNA/proteins of cortical tissues. Cerebrospinal fluid (CSF) of sham and HS rats was also collected before sacrifice. In the HS group, an elevated body temperature (Tco>40°C) and abnormality of cortical cells (e.g., pyknotic nuclei) were observed. When compared to the sham group, expression levels of either mRNAs or proteins of chemokines and their receptors (including CXCL1, MIP2, MCP1, CXCR1, CXCR2, and CCR2) peaked at different time points after heat exposure. We also found that CXCR2 was expressed in the cortex of rat brain and was colocalized with neurons and microglia after HS. Hence, MCP1, MIP2, and CXCR2 might play important roles in the brain after HS, possibly indicating a new direction for treating HS.


Subject(s)
Cerebral Cortex/metabolism , Chemokines/biosynthesis , Heat Stroke/metabolism , Receptors, Chemokine/biosynthesis , Animals , Cerebral Cortex/pathology , Chemokines/analysis , Heat Stroke/pathology , Male , Rats , Rats, Sprague-Dawley , Receptors, Chemokine/analysis
3.
Nature ; 515(7527): 431-435, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25383517

ABSTRACT

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.


Subject(s)
Ischemia/metabolism , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Reperfusion Injury/metabolism , Succinic Acid/metabolism , Adenosine Monophosphate/metabolism , Animals , Aspartic Acid/metabolism , Citric Acid Cycle , Disease Models, Animal , Electron Transport , Electron Transport Complex I/metabolism , Fumarates/metabolism , Ischemia/enzymology , Malates/metabolism , Male , Metabolomics , Mice , Mitochondria/enzymology , Myocardial Infarction/enzymology , Myocardial Infarction/metabolism , Myocardium/cytology , Myocardium/enzymology , Myocardium/metabolism , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/metabolism , NAD/metabolism , Reperfusion Injury/enzymology , Stroke/enzymology , Stroke/metabolism , Succinate Dehydrogenase/metabolism
4.
PLoS One ; 9(4): e94157, 2014.
Article in English | MEDLINE | ID: mdl-24705922

ABSTRACT

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/metabolism , Electron Transport Complex I/deficiency , Animals , Apoptosis/genetics , Cardiomyopathy, Hypertrophic/diagnosis , Disease Models, Animal , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Enzyme Activation , Female , Heart Ventricles/pathology , Hydrogen Peroxide/metabolism , Magnetic Resonance Imaging, Cine , Male , Mice , Mice, Knockout , Mitochondria, Heart/genetics , Mitochondria, Heart/metabolism , Reactive Oxygen Species/metabolism , Severity of Illness Index
5.
PLoS One ; 8(12): e83910, 2013.
Article in English | MEDLINE | ID: mdl-24391843

ABSTRACT

AIM: Stimulation of the nitric oxide (NO)--soluble guanylate (sGC)--protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure. METHODS AND RESULTS: Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and (18)F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5 ± 2.5% of total LV mass vs. 21.8% ± 1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1% ± 3.4% of preischaemic vs. 44.2% ± 3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5% ± 3.2% vs. 48.2% ± 2.2% in control, p = 0.004). CONCLUSION: Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.


Subject(s)
Guanylate Cyclase/metabolism , Heart Failure/prevention & control , Magnetic Resonance Imaging , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Positron-Emission Tomography , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Biomarkers/analysis , Echocardiography , Heart Failure/metabolism , Heart Failure/pathology , Hemodynamics/drug effects , Image Processing, Computer-Assisted , Male , Mice , Mice, Inbred C57BL , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Soluble Guanylyl Cyclase
6.
Shock ; 34(6): 643-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20823696

ABSTRACT

Heat stroke (HS) is defined clinically as a condition when core body temperature rises above 40°C and is accompanied by central nervous system abnormalities. In this study, we established a rat model of HS by exposing anesthetized rats to elevated ambient temperature (40°C) until core temperature reaching 40.5°C (HS onset). The rat was immediately removed from heating chamber, allowed recovery for various time periods, and killed for histological and biochemical studies. Our results indicated neuronal shrinkage and pyknosis of the nucleus and sustained up to 12 h recovery time in cerebral cortex. Elevated expression of autophagy-related proteins, including microtubule associated protein light chain 3 and beclin 1 in cortical tissue at various times (3, 6, 12 h) of recovery was observed. In addition, the number of autophagosomes stained by monodansylcadaverine, a specific autophagosome marker, increased after heat exposure but was reduced by pretreatment with 3-methyladenine, an autophagy inhibitor. Furthermore, heat exposure increased neuronal degeneration in cortical tissue, as evidenced by staining with the fluorescent dye Fluoro-Jade B for degenerating neuron. Pretreatment with 3-methyladenine in HS rats aggravated neurodegeneration. Taken together, these results suggest that HS induces autophagy as a protection mechanism against neurodegeneration. Modulation of autophagy may provide a potential therapeutic approach for HS and await further research.


Subject(s)
Autophagy/physiology , Brain/metabolism , Heat Stroke/physiopathology , Nerve Degeneration/prevention & control , Animals , Cadaverine/analogs & derivatives , Cadaverine/chemistry , Heat Stroke/metabolism , Immunoblotting , Immunohistochemistry , Nerve Degeneration/metabolism , Phagosomes/metabolism , Rats , Rats, Sprague-Dawley
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