Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage.
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ABSTRACT:
SUBMITTER: Veitch K
PROVIDER: S-EPMC1130749 | biostudies-other | 1992 Feb
REPOSITORIES: biostudies-other
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Project description:BACKGROUND AND PURPOSE:Icariin, a major active ingredient in traditional Chinese medicines, is attracting increasing attention because of its unique pharmacological effects against ischaemic heart disease. The histone deacetylase, sirtuin-1, plays a protective role in ischaemia/reperfusion (I/R) injury, and this study was designed to investigate the protective role of icariin in models of cardiac I/R injury and to elucidate the potential involvement of sirtuin-1. EXPERIMENTAL APPROACH:I/R injury was simulated in vivo (mouse hearts), ex vivo (isolated rat hearts) and in vitro (neonatal rat cardiomyocytes and H9c2 cells). Prior to I/R injury, animals or cells were exposed to icariin, with or without inhibitors of sirtuin-1 (sirtinol and SIRT1 siRNA). KEY RESULTS:In vivo and in vitro, icariin given before I/R significantly improved post-I/R heart contraction and limited the infarct size and leakage of creatine kinase-MB and LDH from the damaged myocardium. Icariin also attenuated I/R-induced mitochondrial oxidative damage, decreasing malondialdehyde content and increasing superoxide dismutase activity and expression of Mn-superoxide dismutase. Icariin significantly improved mitochondrial membrane homeostasis by increasing mitochondrial membrane potential and cytochrome C stabilization, which further inhibited cell apoptosis. Sirtuin-1 was significantly up-regulated in hearts treated with icariin, whereas Ac-FOXO1 was simultaneously down-regulated. Importantly, sirtinol and SIRT1 siRNA either blocked icariin-induced cardioprotection or disrupted icariin-mediated mitochondrial homeostasis. CONCLUSIONS AND IMPLICATIONS:Pretreatment with icariin protected cardiomyocytes from I/R-induced oxidative stress through activation of sirtuin-1 /FOXO1 signalling.
| S-EPMC6177614 | biostudies-literature
Project description:Despite improvements in revascularization after a myocardial infarction, coronary disease remains a major contributor to global mortality. Neutrophil infiltration and activation contributes to tissue damage, via the release of myeloperoxidase (MPO) and formation of the damaging oxidant hypochlorous acid. We hypothesized that elevation of thiocyanate ions (SCN-), a competitive MPO substrate, would modulate tissue damage. Oral dosing of rats with SCN-, before acute ischemia-reperfusion injury (30 min occlusion, 24 h or 4 week recovery), significantly reduced the infarct size as a percentage of the total reperfused area (54% versus 74%), and increased the salvageable area (46% versus 26%) as determined by MRI imaging. No difference was observed in fractional shortening, but supplementation resulted in both left-ventricle end diastolic and left-ventricle end systolic areas returning to control levels, as determined by echocardiography. Supplementation also decreased antibody recognition of HOCl-damaged myocardial proteins. SCN- supplementation did not modulate serum markers of damage/inflammation (ANP, BNP, galectin-3, CRP), but returned metabolomic abnormalities (reductions in histidine, creatine and leucine by 0.83-, 0.84- and 0.89-fold, respectively), determined by NMR, to control levels. These data indicate that elevated levels of the MPO substrate SCN-, which can be readily modulated by dietary means, can protect against acute ischemia-reperfusion injury.
| S-EPMC8209016 | biostudies-literature
Project description:ObjectiveBrain damage is universal in the rare survivor of unwitnessed cardiac arrest. Non-pulsatile-controlled cerebral reperfusion offsets this damage, but may simultaneously cause brain oedema when delivered at the required the high mean perfusion pressure. This study analyses pulsatile perfusion first in control pigs and then using controlled reperfusion after prolonged normothermic brain ischaemia (simulating unwitnessed arrest) to determine if it might provide a better method of delivery for brain reperfusion.MethodsInitial baseline studies during isolated brain perfusion in 12 pigs (six non-pulsatile and six pulsatile) examined high (750 cc/min) then low (450 cc/min) fixed flow before and after transient (30 s) ischaemia, while measuring brain vascular resistance and oxygen metabolism. Twelve subsequent pigs underwent 30 min of normothermic global brain ischaemia followed by either uncontrolled reperfusion with regular blood (n = 6) or pulsatile-controlled reperfusion (n = 6) before unclamping brain inflow vessels. Functional neurological deficit score (NDS; score: 0, normal; 500, brain death) was evaluated 24 h post-reperfusion.ResultsHigh baseline flow rates with pulsatile and non-pulsatile perfusion before and after transient ischaemia maintained normal arterial pressures (90-100 mmHg), surface oxygen levels IN Vivo Optical Spectroscopy (INVOS) and oxygen uptake. In contrast, oxygen uptake fell after 30 s ischaemia at 450 cc/min non-pulsatile flow, but improved following pulsatile perfusion, despite its delivery at lower mean cerebral pressure. Uncontrolled (normal blood) reperfusion after 30 min of prolonged ischaemia, caused negligible INVOS O(2) uptake (<10-15%), raised conjugated dienes (CD; 1.75 ± 0.15 A(233 mn)), one early death, multiple seizures, high NDS (243 ± 16) and extensive cerebral infarcts (2,3,5-triphenyl tetrazolium chloride stain) and oedema (84.1 ± 0.6%). Conversely, pulsatile-controlled reperfusion pigs exhibited normal O(2) uptake, low CD levels (1.31 ± 0.07 A(233 mn); P < 0.01 versus uncontrolled reperfusion), no seizures and a low NDS (32 ± 14; P < 0.001 versus uncontrolled reperfusion); three showed complete recovery (NDS = 0) and all could sit and eat. Post-mortem brain oedema was minimal (81.1 ± 0.5; P < 0.001 versus uncontrolled reperfusion) and no infarctions occurred.ConclusionsPulsatile perfusion lowers cerebral vascular resistance and improves global O(2) uptake to potentially offset post-ischaemic oedema following high-pressure reperfusion. The irreversible functional and anatomic damage that followed uncontrolled reperfusion after a 30-min warm global brain ischaemia interval was reversed by pulsatile-controlled reperfusion, as its delivery resulted in consistent near complete neurological recovery and absent brain infarction.
| S-EPMC3327863 | biostudies-literature
Project description: Not available
| S-EPMC6464274 | biostudies-literature
Project description:Ischaemia-reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI-induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R-induced acute renal dysfunction and largely blunted I/R-induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL-positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro-apoptotic alteration of Bcl2/Bax expression, caspase-3 activation, loss of mitochondrial membrane potential and KATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the KATP channel blocker 5-HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post-I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage-associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL-1α, IL-6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1-mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI-induced AKI.
| S-EPMC5661260 | biostudies-literature
Project description:AimsHaem oxygenase-1 (HO-1) is a haem-degrading enzyme that generates carbon monoxide, bilirubin, and iron ions. Through these compounds, HO-1 mitigates cellular injury by exerting antioxidant, anti-apoptotic, and anti-inflammatory effects. Here, we examined the influence of HO-1 deficiency and transient hypoxia/ischaemia-induced HO-1 overexpression on post-injury hindlimb recovery.Methods and resultsMice lacking functional HO-1 (HO-1(-/-)) showed reduced reparative neovascularization in ischaemic skeletal muscles, impaired blood flow (BF) recovery, and increased muscle cell death compared with their wild-type littermates. Human microvascular endothelial cells (HMEC-1) transfected with plasmid vector (pHRE-HO-1) carrying human HO-1 driven by three hypoxia response elements (HREs) and cultured in 0.5% oxygen demonstrated markedly increased expression of HO-1. Such upregulated HO-1 levels were effective in conferring protection against H(2)O(2)-induced cell death and in promoting the proangiogenic phenotype of HMEC-1 cells. More importantly, when delivered in vivo, pHRE-HO-1 significantly improved the post-ischaemic foot BF in mice subjected to femoral artery ligation. These effects were associated with reduced levels of pro-inflammatory cytokines (IL-6 and CXCL1) and lower numbers of transferase-mediated dUTP nick-end labelling-positive cells. Moreover, HO-1 delivered into mouse skeletal muscles seems to influence the regenerative potential of myocytes as it significantly changed the expression of transcriptional (Pax7, MyoD, myogenin) and post-transcriptional (miR-146a, miR-206) regulators of skeletal muscle regeneration.ConclusionOur results suggest the therapeutic potential of HO-1 for prevention of adverse effects in critical limb ischaemia.
| S-EPMC3527762 | biostudies-literature
Project description:Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.
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Project description:Platelets are classically known for their roles in bleeding control and occlusive thrombus formation causing ischaemic tissue damage. Recently non-classical roles for platelets have been described, many of which may be mediated by the heterogeneous cargo that platelets secrete from granular stores upon activation. Using an in vitro model of ischaemic injury to ventricular cardiomyocytes, we observed that platelets, through secreted factors, delayed the rate of cardiomyocyte death during ischaemia. This protective effect appeared independent of platelet dense granule cargo, but required α-granule components stromal cell-derived factor (SDF)-1α and transforming growth factor (TGF) β1. Protein kinase C (PKC) activity within cardiomyocytes was responsible for mediating the protective signals initiated by the released platelet cargo. Importantly, pretreating platelets with a P2Y12 antagonist, but not the cyclooxygenase inhibitor aspirin, substantially attenuated this protective effect. These findings therefore reveal a paradoxically protective role for platelet activation during cardiac ischaemia and could have important implications for the use of anti-platelet therapeutics in the management of myocardial infarction.
| S-EPMC6241850 | biostudies-literature
Project description:Comprehensive understanding of the transcriptional foundations of human intestinal ischemia-reperfusion (IR) injury is imperative to find therapeutic targets and improve patient outcome. Here we analysed transcriptomes of the IR-injured human intestine, and showed that over 1,800 genes were significantly differentially expressed, predominantly during reperfusion. Intriguingly, protein processing in endoplasmic reticulum (ER) was one of the most perturbed pathways, which was supported by ontology analysis. The IR-triggered transcriptome is organized into distinct co-expression networks, and implied a role for HIF1-alpha in the response towards unfolded proteins. Unfolded protein response activation as a consequence of ER stress was further validated in a large sample set, revealing strong correlations between expression of ER stress genes IRE1, XBP1 and BiP and autophagy gene LC3B. Moreover, signs of ER stress and autophagy, particularly ER phagy, were apparent in Paneth cells. Collectively, these findings provide new evidence for key involvement of protein folding stress in IR-induced intestinal injury in man. The ensuing ER stress, together with its manifestations in Paneth cells, likely contributes to IR-induced complications including bacterial penetration and inflammation.
2021-11-11 | GSE37013 | GEO
Project description:Respiratory NADH oxidation in the rumen bacterium Prevotella bryantii is catalyzed by the Na+-translocating NADH:quinone oxidoreductase (NQR). A method for cell disruption and membrane isolation of P. bryantii under anoxic conditions using the EmulisFlex-C3 homogenizer is described. We compared NQR activity and protein yield after oxic and anoxic cell disruption by the EmulsiFlex, by ultrasonication, and by glass beads treatment. With an overall membrane protein yield of 50 mg L-1 culture and a NADH oxidation activity of 0.8 µmol min-1 mg-1, the EmulsiFlex was the most efficient method. Anoxic preparation yielded fourfold higher NQR activity compared to oxic preparation. P. bryantii lacks genes coding for superoxide dismutases and cell extracts do not exhibit superoxide dismutase activity. We propose that inactivation of NQR during oxic cell rupture is caused by superoxide, which accumulates in P. bryantii extracts exposed to air. Anoxic cell rupture is indispensable for the preparation of redox-active proteins and enzymes such as NQR from P. bryantii.
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