Lethal Ischemia Research Articles

Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10min; (3) MCAO/R group: left middle cerebral artery was blocked for 90min; (4) CIP + MCAO/R group: CIP was performed 72h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

Trends in population-based incidence, diagnostics, and mortality of acute superior mesenteric artery occlusion.

Acute occlusion of the superior mesenteric artery (SMA) results in lethal intestinal ischemia. Results from two previous population-based studies in Malmö, Sweden, suggest a decreasing incidence of acute SMA occlusion. This study aimed to evaluate trends in the epidemiology of acute SMA occlusion in Malmö. The report was a retrospective population-based study conducted from 2014 to 2019 on patients with acute SMA occlusion residing in Malmö municipality. Patient data were retrieved from Skåne University Hospital and postmortem examinations. Epidemiological data were compared to those of the two earlier studies, in particular to the one conducted from 2000 to 2006. Sixteen patients with acute SMA occlusion resided in Malmö municipality. The incidence of acute SMA occlusion significantly decreased from 5.4/100,000 person-years to 0.8/100,000 person-years. The ratio of acute SMA occlusion to non-occlusive mesenteric ischemia (NOMI) decreased from 12.5:1 to 0.9:1 (p < 0.0001), the proportion of inhabitants aged 80 years or above in the population decreased from 6.0% to 4.3% (p < 0.0001), and the autopsy rate decreased from 25% to 14% (p < 0.0001). The in-hospital mortality rate decreased from 63% to 44% (p = 0.14). The incidence of acute SMA occlusion seems to have decreased significantly in Malmö, probably due to high-resolution computed tomography angiographies being available around the clock to distinguish acute SMA occlusion from NOMI, a reduced proportion of elderly individuals, improved control of medical risk factors, and a decrease in autopsy rates.

Quantitative analysis of selected genetic markers of induced brain stroke ischemic tolerance detected in human blood

A brain stroke is a serious disease and the second leading cause of death in the European Union. Carotid stenosis accounts for 15% of all ischemic cerebral strokes. However, there is currently no effective screening for carotid disease. Analysis of the DNA from peripheral blood is increasingly being used for several disease diagnoses. The potentially beneficial therapeutic method of inducing tissue tolerance to ischemia has so far been studied mainly in animal models. The aim of this study is to investigate changes in the gene expression of selected markers of brain ischemia during carotid endarterectomy, considered in this study as an activator of ischemic tolerance. During the carotid endarterectomy, there is a short-term occlusion of the internal carotid artery. Using the RT-qPCR method, we detected changes in the early identified gene markers of brain ischemia (ADM, CDKN1A, GADD45G, IL6, TM4SF1) in peripheral blood during sub lethal cerebral ischemia caused by carotid endarterectomy. Patients underwenting surgical procedure were divided into three groups: asymptomatic, symptomatic, and those who underwent carotid endarterectomy after an acute stroke. The results were compared to a negative/control group. Carotid endarterectomy had an impact on the expression of all monitored biomarkers. We observed statistically significant changes (p value 0.05–0.001) when comparing the groups among themselves, as well as the presence of ischemic tolerance of brain tissue to ischemic attacks. In conclusion, ADM, GADD45G, and TM4SF1 were affected in symptomatic patients, GADD45G and IL6 in acute patients, and CDKN1A and ADM in asymptomatic group after application of carotid endarterectomy.

Single-Dose Treatment with Rapamycin Preserves Post-Ischemic Cardiac Function through Attenuation of Fibrosis and Inflammation in Diabetic Rabbit.

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial ischemia/reperfusion (I/R) injury in diabetic rabbits. Diabetic rabbits (DM) were subjected to 45 min of ischemia and 10 days of reperfusion by inflating/deflating a previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before the onset of reperfusion. Post-I/R left ventricular (LV) function was assessed by echocardiography and fibrosis was evaluated by picrosirius red staining. Treatment with RAPA preserved LV ejection fraction and reduced fibrosis. Immunoblot and real-time PCR revealed that RAPA treatment inhibited several fibrosis markers (TGF-β, Galectin-3, MYH, p-SMAD). Furthermore, immunofluorescence staining revealed the attenuation of post-I/R NLRP3-inflammasome formation with RAPA treatment as shown by reduced aggregation of apoptosis speck-like protein with a caspase recruitment domain and active-form of caspase-1 in cardiomyocytes. In conclusion, our study suggests that acute reperfusion therapy with RAPA may be a viable strategy to preserve cardiac function with the alleviation of adverse post-infarct myocardial remodeling and inflammation in diabetic patients.

Ischemic Tolerance—A Way to Reduce the Extent of Ischemia–Reperfusion Damage

Individual tissues have significantly different resistance to ischemia-reperfusion damage. There is still no adequate treatment for the consequences of ischemia-reperfusion damage. By utilizing ischemic tolerance, it is possible to achieve a significant reduction in the extent of the cell damage due to ischemia-reperfusion injury. Since ischemia-reperfusion damage usually occurs unexpectedly, the use of preconditioning is extremely limited. In contrast, postconditioning has wider possibilities for use in practice. In both cases, the activation of ischemic tolerance can also be achieved by the application of sublethal stress on a remote organ. Despite very encouraging and successful results in animal experiments, the clinical results have been disappointing so far. To avoid the factors that prevent the activation of ischemic tolerance, the solution has been to use blood plasma containing tolerance effectors. This plasma is taken from healthy donors in which, after exposure to two sublethal stresses within 48 h, effectors of ischemic tolerance occur in the plasma. Application of this activated plasma to recipient animals after the end of lethal ischemia prevents cell death and significantly reduces the consequences of ischemia-reperfusion damage. Until there is a clear chemical identification of the end products of ischemic tolerance, the simplest way of enhancing ischemic tolerance will be the preparation of activated plasma from young healthy donors with the possibility of its immediate use in recipients during the initial treatment.

Abstract WMP112: Type 2 Diabetes Dampens Neuroprotection Against Ischemic Injury By Lipopolysaccharide-Induced Preconditioning

Introduction: Evidence suggests that lipopolysaccharide ( LPS ) preconditioning (PC) provides neuroprotection by inducing tolerance to subsequent lethal ischemia. Ischemic tolerance (IT) declines with age, yet it is unclear whether metabolic disease like type 2 diabetes (T2DM) also interfere with IT. The current study sought to determine whether T2DM reduces neuroprotection induced by LPS PC, and the molecular mechanisms underlying the dampened IT. Methods: Male and female diabetic db/db and control db/+ mice (8-10 months of age) were i.p. injected with Toll-like receptor (TLR)4 ligand LPS at 0.2 mg/kg or saline. Stroke was induced 3 days later by permanent distal occlusion of middle cerebral artery and temporary occlusion of ipsilateral common carotid artery for 60 min. Sensory and motor function was evaluated 1 day after stroke by a combination of tests. Infarct size was determined 3 days after stroke following TTC staining. The effect of LPS PC on the phenotypes of leukocytes in the brain parenchyma after stroke was quantified by Fluorescent activated cell sorter (FACS) 2 days after stroke with a panel of markers for subsets of myeloid cells. Transcriptome was determined by RNAseq of isolated monocytes from peripheral blood mononuclear cells. Differentially expressed genes were examined for distinct biological pathways via enrichment analysis. Results: LPS PC significantly reduced infarct in db/+ mice by one third and improved neurological scores, but it did not protect the db/db mice from stroke. FACS data showed that LPS PC reduced the number of Ly6G+ cells in db/+ but not db/db brains, suggesting that LPS PC curbed stroke-induced infiltration of neutrophils in the brain parenchyma. Pathway analysis suggests that diabetic mice exhibited down-regulated pathways in interferon signaling. The expression of Jak-Stat signaling (such as Stat1), MHC antigen presentation (H2A family), and Toll-like receptor (TLR) signaling (such as Irf7) were also reduced in diabetic mice after stroke. Conclusions: The dampened IT in the diabetic mice induced by LPS-PC is associated with increased neutrophil infiltration after stroke compared to control mice. Ongoing studies will seek toovercome the underlying defective molecular mechanisms in T2DM.

CPKCγ-Modulated Autophagy Contributes to Ischemic Preconditioning-Induced Neuroprotection in Mice with Ischemic Stroke via mTOR-ULK1 Pathway.

Neuron-specific conventional protein kinase C (cPKC)γ mediates cerebral hypoxic preconditioning (HPC). In parallel, autophagy plays a prosurvival role in ischemic preconditioning (IPC) against ischemic stroke. However, the effect of cPKCγ on autophagy in IPC still remains to be addressed. In this study, adult and postnatal 1-day-old C57BL/6J wild-type (cPKCγ+/+) and knockout (cPKCγ-/-) mice were used to establish in vivo and in vitro IPC models. The results showed that IPC pretreatment alleviated neuronal damage caused by lethal ischemia, which could be suppressed by autophagy inhibitor 3-MA or bafilomycin A1. Meanwhile, cPKCγ knockout blocked IPC-induced neuroprotection, accompanied by significant increase of LC3-I to LC3-II conversion and Beclin 1 protein level, and a significant decrease in p62 protein level. Immunofluorescent staining results showed a decrease of LC3 puncta numbers in IPC-treated cPKCγ+/+ neurons with fatal ischemia, which was reversed in cPKCγ-/- neurons. In addition, cPKCγ-modulated phosphorylation of mTOR at Ser 2448 and ULK1 at Ser 555, rather than p-Thr-172 AMPK, was detected in IPC-pretreated neurons upon lethal ischemic exposure. The present data demonstrated that cPKCγ-modulated autophagy via the mTOR-ULK1 pathway likely modulated IPC-induced neuroprotection.

Klotho Upregulation via PPARγ Contributes to the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning in Rats.

Cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance protects neurons from subsequent lethal ischemic insult. However, the specific mechanisms underlying CIP remain unclear. In the present study, we explored the hypothesis that peroxisome proliferator-activated receptor gamma (PPARγ) participates in the upregulation of Klotho during the induction of brain ischemic tolerance by CIP. First we investigated the expression of Klotho during the brain ischemic tolerance induced by CIP. Lethal ischemia significantly decreased Klotho expression from 6h to 7days, while CIP significantly increased Klotho expression from 12h to 7days in the hippocampal CA1 region. Inhibition of Klotho expression by its shRNA blocked the neuroprotection induced by CIP. These results indicate that Klotho participates in brain ischemic tolerance by CIP. Furthermore, we tested the role of PPARγ in regulating Klotho expression after CIP. CIP caused PPARγ protein translocation to the nucleus in neurons in the CA1 region of the hippocampus. Pretreatment with GW9962, a PPARγ inhibitor, significantly attenuated the upregulation of Klotho protein and blocked the brain ischemic tolerance induced by CIP. Taken together, it can be concluded that Klotho upregulation via PPARγ contributes to the induction of brain ischemic tolerance by CIP.

High take-off of coronary arteries contributing to lethal myocardial ischemia: report of two cases

Abstract Introduction/Objective High take-off coronary arteries (HTO) are defined by coronary ostia arising above the sinotubular junction (STJ). Although asymptomatic in most individuals, there is increasing evidence that HTO is a risk factor for sudden cardiac death. Here we present two patients where HTO contributed to death. Methods/Case Report Patient A was a 52 year old morbidly obese male with atypical chest pain, new inferior ST elevations and troponinemia. Multiple coronary angiographies did not reveal any stenosis, but 3 stents were placed in the RCA due to concern for vasospasm. 3 days later the patient died. Autopsy revealed cardiac tamponade and non- atherosclerotic ischemic heart disease with remote apical LV scar and diffuse patchy interstitial fibrosis in the myocardium, which could be attributed to HTO of the RCA 0.5 cm above the STJ and early intramuscular courses of both coronaries. Multiple angiographies likely caused iatrogenic coronary injury and subsequent tamponade. Patient B was a healthy 33 year old female at 34 weeks gestation, who developed anaphylaxis during IV iron infusion for severe iron deficiency anemia. She was transferred to the OR for emergent C-section. Minutes after delivery she died. Autopsy revealed HTO, with coronary ostia being 0.4 cm and 0.7 cm above the STJ, respectively and acute angle take-off of LCA. No atherosclerosis was noted. The inability to increase myocardial perfusion through the coronary arteries during a high stress situation due to pregnancy, iron deficiency anemia and anaphylaxis likely contributed to lethal myocardial ischemia. Results (if a Case Study enter NA) NA Conclusion HTO and other coronary artery anomalies (CAAs) should be considered in cases of cryptogenic acute and chronic myocardial ischemia. Hemodynamic characterization of HTO, including those &amp;lt; 1 cm above the STJ in presence and absence of other CAAs may help better understand their pathophysiologic significance. Antemortem diagnosis requires high clinical suspicion and appropriate surgical intervention could be life-saving.

MiR-182 Promotes Ischemia/Reperfusion-Induced Acute Kidney Injury in Rat by Targeting FoxO3

Background: Renal ischemia/reperfusion (I/R) injury (RIRI) is the main cause of acute kidney injury (AKI) in patients. We investigated the role of miR-182 after renal ischemia/reperfusion (I/R) in rat to characterize the microRNA (miRNA) network activated during development and recovery from RIRI. Methods and Results: 12 h after lethal (45 min) renal ischemia, AKI was verified by renal histology (tubular necrosis and regeneration), blood urea nitrogen level, and renal mRNA expression in Wistar rats. We found that miR-182 markedly increased after renal I/R. In cell hypoxia/reoxygenation model, we found similar upregulation of miR-182. In function gain/loss assay, we confirmed an impaired effect of miR-182 and identified Forkhead box O3 (FoxO3) as a direct downstream target of it. By using miR-182 antagomir, the I/R injury was markedly ameliorated. Conclusions: Our results demonstrate that miR-182 promotes cell apoptosis and I/R injury through directly binding to FoxO3. The present study will provide potential therapeutic targets for renal I/R-induced AKI, and open a new avenue for AKI treatment by manipulating miRNAs levels.

Beclin-1/LC3-II dependent macroautophagy was uninfluenced in ischemia-challenged vascular endothelial cells

Autophagy has been extensively studied and occurs in many biological settings. However, a question remains as to whether ischemia enhances Beclin-1/LC3-II-dependent macroautophagy in vascular endothelial cells, as has been previously thought. Furthermore, the effect of the level of autophagy on cell or skin flap survival still requires elucidation. We created a lethal ischemia model in human umbilical vascular endothelial cells (HUVECs), performed quantitative proteomics and bioinformatics analyses, and verified the autophagic status and effect both in vitro and in vivo. The significantly upregulated proteins encoded by autophagy-related genes (ATGs) included ATG2A, ATG3, ATG4B, ATG5, ATG7, ATG9A, ATG12, ATG16, and ATG101. The significantly enhanced lysosomal proteins were cathepsin B, cathepsin D, lysosome-associated membrane protein 1 (LAMP1), and LAMP2. However, the differentially expressed proteins excluded Beclin-1, microtubule-associated protein light chain 3 (LC3)-I, and LC3-II. Western blot analyses verified that the protein expression levels of Beclin-1, LC3-I, and LC3-II were neither upregulated nor downregulated in ischemia-challenged HUVECs. The autophagic status was not enhanced by rapamycin in ischemic HUVECs but appeared to be inhibited by chloroquine. Our in vivo study on rats showed that a downregulation in autophagic status jeopardized skin flap survival. In conclusion, Ischemia neither enhanced nor inhibited Beclin-1/LC3-II-dependent canonical macroautophagy both in vitro and in vivo, in contradiction to previous studies. An appropriate autophagic homeostasis can minimize cell or skin flap damage.

Robotic Distal Gastrectomy for Advanced Gastric Cancer After Coronary Artery Bypass Grafting Using the Right Gastroepiploic Artery

Introduction The right gastroepiploic artery (RGEA) is used in coronary artery bypass grafting (CABG). However, the treatment of gastric cancer after CABG using the RGEA is complex, because stopping coronary blood flow from the RGEA may cause lethal myocardial ischemia. Adequate treatment must strike a balance between the curability and safety. Case Presentation The patient was a 79-year-old man with advanced gastric cancer who had previously undergone CABG with the RGEA. It was impossible to perform curative gastrectomy with preservation of the RGEA. Thus, percutaneous coronary intervention was performed to revascularize the native right coronary artery. The patient then started chemotherapy using oxaliplatin and S-1. After 4 courses of chemotherapy, the patient underwent robotic distal gastrectomy with D2 lymphadenectomy, including regional lymph node dissection around the RGEA. The RGEA was cut after a clamp test confirmed that there was no ST change. Conclusion In patients who develop gastric cancer after CABG using the RGEA, percutaneous coronary intervention of the native coronary artery is useful when resection of the RGEA is required to dissect the No. 6 lymph node. Robotic gastrectomy is a surgical option in such cases.

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke.

Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke.

Simulation of Blood as Fluid: A Review From Rheological Aspects.

Blood flow in the human vascular system is a complex to understand example of fluid dynamics in a closed conduit. Any irregularities in the hemodynamics may lead to lethal cardiovascular disease like heart attack, heart failure and ischemia. Numerical simulation of hemodynamics in the blood vessel can facilitate a thorough understanding of blood flow and its interaction with the adjacent vessel wall. A good simulation approach for blood flow can be helpful in early prediction and diagnosis of the mentioned disease. The simulation outcomes may also provide decision support for surgical planning and medical implants. This study reports an extensive review of various approaches adopted to analyze the influence of blood rheological characteristics in a different class of blood vessels. In particular, emphasis was given on the identification of best possible rheological model to effectively solve the hemodynamics inside different blood vessels. The performance capability of different rheological models was discussed for different classes and conditions of vessels and the best/poor performing models are listed out. The Carreau, Casson and generalized power-law models were appeared to be superior for solving the blood flow at all shear rates. In contrast, power law, Walburn-Scheck and Herchel-Bulkley model lacks behind in the purpose.

Protective effects of ischemic preconditioning against neuronal apoptosis and dendritic injury in the hippocampus are age-dependent.

Ischemic preconditioning with non-lethal ischemia can be protective against lethal forebrain ischemia. We hypothesized that aging may aggravate ischemic susceptibility and reduce brain plasticity against preconditioning. Magnetic resonance diffusion tensor imaging (DTI) is a sensitive tool to detect brain integrity and white matter architecture. This study used DTI and histopathology to investigate the effect of aging on ischemic preconditioning. In this study, adult and middle-aged male Mongolian gerbils were subjected to non-lethal 5-min forebrain ischemia (ischemic preconditioning) or sham-operation, followed by 3days of reperfusion, and then lethal 15-min forebrain ischemia. A 9.4-Tesla MR imaging system was used to study DTI indices, namely fractional anisotropy (FA), mean diffusivity (MD), and intervoxel coherence (IC) in the hippocampal CA1 and dentate gyrus (DG) areas. In situ expressions of microtubule-associated protein 2 (MAP2, dendritic marker protein) and apoptosis were also examined. The 5-min ischemia did not cause dendritic and neuronal injury and any significant change in DTI indices and MAP2 in adult and middle-aged gerbils. The 15-min ischemia-induced significant delayed neuronal apoptosis and early dendritic injury evidenced by DTI and MAP2 studies in both CA1 and DG areas with more severe injury in middle-aged gerbils than adult gerbils. Ischemic preconditioning could improve neuronal apoptosis in CA1 area and dendritic integrity in both CA1 and DG areas with better improvement in adult gerbils than middle-aged gerbils. This study thus suggests an age-dependent protective effect of ischemic preconditioning against both neuronal apoptosis and dendritic injury in hippocampus after forebrain ischemia.

Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death.

Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous studies have focused on rescuing neural cells that still survive despite decreased blood flow, expanding the therapeutic time window may allow more patients to undergo reperfusion in the near future, even after lethal ischemia, which is characterized by death of mature neural cells, such as neurons and glia. However, it remains unclear whether early reperfusion following lethal ischemia results in positive outcomes. The present study used two ischemic mouse models—90-min transient middle cerebral artery occlusion (t-MCAO) paired with reperfusion to induce lethal ischemia and permanent middle cerebral artery occlusion (p-MCAO)—to investigate the effect of early reperfusion up to 8 w following MCAO. Although early reperfusion following 90-min t-MCAO did not rescue mature neural cells, it preserved the vascular cells within the ischemic areas at 1 d following 90-min t-MCAO compared to that following p-MCAO. In addition, early reperfusion facilitated the healing processes, including not only vascular but also neural repair, during acute and chronic periods and improved recovery. Furthermore, compared with p-MCAO, early reperfusion after t-MCAO prevented behavioral symptoms of neurological deficits without increasing negative complications, including hemorrhagic transformation and mortality. These results indicate that early reperfusion provides beneficial effects presumably via cytoprotective and regenerative mechanisms in the CNS, suggesting that it may be useful for stroke patients that experienced lethal ischemia.

Time-course pattern of neuronal death and gliosis in gerbil hippocampi induced by mild, severe and lethal transient global cerebral ischemia

Background: Transient ischemia (TI) in whole brain brings selective neuronal death in vulnerable areas of the brain: the striatum, neocortex and hippocampus selectively loose specific neurons after TI. Just 5 min of TI causes pyramidal neuronal death in the hippocampal CA1 field (CA1) from 4 days after TI. In this study, we examined the impact of severity of TI on neuronal death and gliosis (astrocytosis and microgliosis) in subregions (CA1-3 fields and dentate gyrus) of the gerbil hippocampal formation after 5 min (mild), 15 min (severe) and 20 min (lethal) TI by bilateral carotid artery occlusion (BCCAO).

Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective.

Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body's vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy's effects on the vascular system. An ancient Indian form of exercise called 'yoga' causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia-reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti-pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti-inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow-derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior's role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

A case of blunt thoracic aortic injury requiring ECMO for acute malperfusion before TEVAR

BackgroundBlunt thoracic aortic injury (BTAI) is associated with a high mortality rate and the paradigm of treating patients with BTAI currently favours thoracic endovascular aneurysm repair (TEVAR) if possible. In BTAI, lethal malperfusion caused by a pseudoaneurysm has rarely been reported. We present the first report of a successful case in which a pseudoaneurysm causing the infrequent occurrence of lethal malperfusion and subsequent acute severe ischaemia in the distal portion of the thoracic descending aorta was overcome by veno-arterial extracorporeal membrane oxygenation (VA ECMO) as a bridging therapy until the initiation of TEVAR.Case presentationAn adult woman was transferred to our emergency room after injuries sustained by falling from height. Her vital signs were unstable on admission. CT examination revealed the multiple injuries: traumatic subarachnoid haemorrhage, severe unstable pelvic fracture, and a grade III injury of the thoracic aorta. We made the decision to perform TEVAR after external fixation and transcatheter arterial embolization (TAE) for the pelvic injury. During preparations for TEVAR, her lower limbs rapidly felt cold, and her blood lactate level and serum potassium rapidly increased. By the clinical data and ultrasonography and lower extremity Doppler, we diagnosed severe ischaemia in distal portion of the descending aorta caused by a pseudoaneurysm proximal to the descending thoracic aorta. Because we still had not prepared for TEVAR, we immediately started VA ECMO until TEVAR could begin. After the initiation of VA ECMO, her lactate and potassium levels could be controlled. Under VA ECMO support, she underwent TEVAR. After inpatient rehabilitation, she was discharged home without neurologic sequelae.ConclusionsVA ECMO could be an important, less-invasive treatment as a bridging therapy for acute severe malperfusion syndrome until TEVAR is initiated for BTAI.

Role of PI3K in myocardial ischaemic preconditioning: mapping pro-survival cascades at the trigger phase and at reperfusion.

The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro‐survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K‐Akt, its negative regulator PTEN and other pro‐survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K‐dependent during the IPC phase. In conclusion, PI3K‐Akt plays a major role in IPC‐induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K‐independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade.