Redox Paradox: Can Hypoxia Heal Ischemic Hearts?
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SUBMITTER: Guimaraes-Camboa N
PROVIDER: S-EPMC5547440 | biostudies-other | 2016 Nov
REPOSITORIES: biostudies-other
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Project description:It has been shown that the adeno-associated virus (AAV) vector can deliver the VEGF gene efficiently into the ischemic mouse myocardium. However, the AAV genomes can be found in extracardiac organs after intramyocardial injection. To limit unwanted VEGF expression in organs other than the heart, we tested the use of the cardiac myosin light chain 2v (MLC-2v) promoter and the hypoxia-response element to mediate cardiac-specific and hypoxia-inducible VEGF expression. An AAV vector, MLCVEGF, with 250 bp of the MLC-2v promoter and nine copies of the hypoxia-response element driving VEGF expression, was constructed. Gene expression was studied in vitro by infection of rat cardiomyocytes, rat skeletal myocytes, and mouse fibroblasts with the vector and in vivo by direct injection of the vector into normal and ischemic mouse hearts. With MLCVEGF infection, VEGF expression was higher in cardiomyocytes than the other two cell lines and was hypoxiainducible. VEGF expression was also higher in ischemic hearts than in normal hearts. No VEGF expression was detectable in organs with detectable MLCVEGF vectors other than the heart. MLCVEGF-injected ischemic hearts had more capillaries and small vessels around the injection site, smaller infarct size, and better cardiac function than the negative controls. Hence, MLCVEGF can mediate cardiac-specific and hypoxia-inducible VEGF expression, neoangiogenesis, infarct-size reduction, and cardiac functional improvement.
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Project description:Ischemic cardiomyopathy (ICM) is associated with abnormal microRNA expression levels that involve an altered gene expression profile. However, little is known about the underlying causes of microRNA disruption in ICM and whether microRNA maturation is compromised. Therefore, we focused on microRNA maturation defects analysis and the implication of the microRNA biogenesis pathway and redox-sensitive microRNAs (redoximiRs). Transcriptomic changes were investigated via ncRNA-seq (ICM, n = 22; controls, n = 8) and mRNA-seq (ICM, n = 13; control, n = 10). The effect of hypoxia on the biogenesis of microRNAs was evaluated in the AC16 cell line. ICM patients showed a reduction in microRNA maturation compared to control (4.30 ± 0.94 au vs. 5.34 ± 1.07 au, p ˂ 0.05), accompanied by a deregulation of the microRNA biogenesis pathway: a decrease in pre-microRNA export (XPO5, FC = -1.38, p ˂ 0.05) and cytoplasmic processing (DICER, FC = -1.32, p ˂ 0.01). Both processes were regulated by hypoxia in AC16 cells (XPO5, FC = -1.65; DICER1, FC = -1.55; p ˂ 0.01; Exportin-5, FC = -1.81; Dicer, FC = -1.15; p ˂ 0.05). Patients displayed deregulation of several redoximiRs, highlighting miR-122-5p (FC = -2.41, p ˂ 0.001), which maintained a good correlation with the ejection fraction (r = 0.681, p ˂ 0.01). We evidenced a decrease in microRNA maturation mainly linked to a decrease in XPO5-mediated pre-microRNA export and DICER1-mediated processing, together with a general effect of hypoxia through deregulation of biogenesis pathway and the redoximiRs.
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Project description:SignificanceCancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies.Critical issuesThe major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment.Future directionsBased on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.
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Project description:Background and Purpose- The location of the thrombus as observed on first digital subtraction angiography during endovascular treatment may differ from the initial observation on initial noninvasive imaging. We studied the incidence of thrombus dynamics, its impact on patient outcomes, and its association with intravenous thrombolytics. Methods- We included patients from the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke) with an initial target occlusion on computed tomography angiography located in the intracranial internal carotid artery, M1, or M2. The conventional angiography target occlusion was defined during endovascular treatment. Thrombus dynamics were classified as growth, stability, migration, and resolution. The primary outcome was functional outcome at 90 days (modified Rankin Scale). The secondary outcomes were successful and complete reperfusion (extended treatment in cerebral infarction scores of 2b-3 and 3, respectively). Results- The analysis included 1349 patients. Thrombus migration occurred in 302 (22%) patients, thrombus growth in 87 (6%), and thrombus resolution in 39 (3%). Intravenous treatment with alteplase was associated with more thrombus migration (adjusted odds ratio, 2.01; CI, 1.29-3.11) and thrombus resolution (adjusted odds ratio, 1.85; CI, 1.22-2.80). Thrombus migration was associated with a lower chance of complete reperfusion (adjusted odds ratio, 0.57; CI, 0.42-0.78) and successful reperfusion (adjusted odds ratio, 0.74; CI, 0.55-0.99). In the subgroup of patients with M1 initial target occlusion, thrombus migration was associated with better functional outcome (adjusted common odds ratio, 1.49; CI, 1.02-2.17), and there was a trend towards better functional outcome in patients with thrombus resolution (adjusted common odds ratio, 2.23; CI, 0.93-5.37). Conclusions- In patients with acute ischemic stroke, thrombus location regularly changes between computed tomography angiography and digital subtraction angiography. Administration of intravenous alteplase increases the chance of thrombus migration and resolution. Thrombus migration is associated with better functional outcome but reduces the rate of complete reperfusion.
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Project description:Oxidative stress contributes to detrimental functional decline of the myocardium, leading to the impairment of the antioxidative defense, dysregulation of redox signaling, and protein damage. In order to precisely dissect the changes of the myocardial redox state correlated with oxidative stress and heart failure, we subjected left-ventricular tissue specimens collected from control or failing human hearts to comprehensive mass spectrometry-based redox and quantitative proteomics, as well as glutathione status analyses. As a result, we report that failing hearts have lower glutathione to glutathione disulfide ratios and increased oxidation of a number of different proteins, including constituents of the contractile machinery as well as glycolytic enzymes. Furthermore, quantitative proteomics of failing hearts revealed a higher abundance of proteins responsible for extracellular matrix remodeling and reduced abundance of several ion transporters, corroborating contractile impairment. Similar effects were recapitulated by an in vitro cell culture model under a controlled oxygen atmosphere. Together, this study provides to our knowledge the most comprehensive report integrating analyses of protein abundance and global and peptide-level redox state in end-stage failing human hearts as well as oxygen-dependent redox and global proteome profiles of cultured human cardiomyocytes.
| S-EPMC7916846 | biostudies-literature
Project description:Pre-LVAD and explanted ischemic and nonischemic cardiomyopathy and nonfailing hearts all normalized with RMA Keywords: other
2004-10-26 | GSE1869 | GEO
Project description:BackgroundTibetan pigs have exhibited unique characteristics from low-altitudes pigs and adapted well to the Qinghai-Tibet Plateau.ObjectivesThe current study was undertaken to investigate the hypoxic adaptation of heart in Tibetan pigs.MethodsThe hearts of Tibetan pigs and Landrace pigs raised at high or low altitudes were compared using 3D casting technology, scanning electron microscopy and real-time quantitative PCR (qRT-PCR).ResultsWe found that the ratio of the major axis to the minor axis and the density of the heart were significantly higher in Tibetan pigs than in Landrace pigs (p < 0.05). Tibetan pigs had larger diameters and higher densities of arterioles than Landrace pigs (p < 0.05), and these features have a similar variation with the expression of vascular endothelial growth factor (VEGF). The cardiac expression levels of hypoxia-inducible factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) were significantly higher in pigs reared at high altitudes than in those reared at low altitudes (p < 0.05). In contrast, Egl nine homolog 1 (EGLN1) had the opposite trend with respect to HIF-1α and eNOS and was related to red blood cell (RBC) counts. Notably, the expressions of erythropoietin (EPO) and endothelial PAS domain-containing protein 1 (EPAS1) were significantly higher in Landrace pigs kept at high altitudes than in the others (p < 0.05) and were associated with haemoglobin.ConclusionsThese findings show that the regulation of the heart function of Tibetan pigs in a hypoxic environment is manifested at various levels to ensure the circulation of blood under extreme environmental conditions.
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Project description: Not available
| S-DIXA-D-1049 | biostudies-other
Project description:Background: Low lipid level is associated with better cardiovascular outcome. However, lipid paradox indicating low lipid level having worse outcomes could be seen under acute injury in some diseases. The present study was designed to clarify the prognostic significance of acute-phase lipid levels within 1 day after admission for stroke on mortality in first-ever statin-naïve acute ischemic stroke (IS) and hemorrhagic stroke (HS). Methods: This observational study was conducted using the data collected from Stroke Registry In Chang-Gung Healthcare System (SRICHS) between 2009 and 2012. Patients with recurrent stroke, onset of symptoms >1 day, and history of the use of lipid-lowering agents prior to index stroke were excluded. Stroke was classified into IS and hypertension-related HS. The primary outcomes were 30-day and 1-year mortality identified by linkage to national death registry for date and cause of death. Receiver operating characteristic (ROC) curve analysis and multivariate Cox proportional hazard models were used to examine the association of lipid profiles on admission with mortality. Results: Among the 18,268 admitted stroke patients, 3,746 IS and 465 HS patients were eligible for analysis. In IS, total cholesterol (TC) <163.5 mg/dL, triglyceride (TG) <94.5 mg/dL, low-density lipoprotein (LDL) <100 mg/dL, non-high-density lipoprotein cholesterol (non-HDL-C) <130.5 mg/dL, and TC/HDL ratio <4.06 had significantly higher risk for 30-day/1-year mortality with hazard ratio (HR) of 2.05/1.37, 1.65/1.31, 1.68/1.38, 1.80/1.41, and 1.58/1.38, respectively, compared with high TC, TG, LDL, non-HDL-C, and TC/HDL ratio (p < 0.01 in all cases). In HS, lipid profiles were not associated with mortality, except HDL for 30-day mortality (p = 0.025) and high uric acid (UA) concentrations for 30-day and 1-year mortality (p = 0.002 and 0.012, respectively). High fasting glucose and high National Institute of Health Stroke Scale (NIHSS) score at admission were associated with higher 30-day and 1-year mortality in both IS and HS and low blood pressure only in IS (p < 0.05). Synergic effects on mortality were found when low lipids were incorporated with high fasting glucose, low blood pressure, and high NIHSS score in IS (p < 0.05). Conclusions: Lipid paradox showing low acute-phase lipid levels with high mortality could be seen in statin-naïve acute IS but not in HS. The mortality in IS was increased when low lipids were incorporated with high fasting glucose, low blood pressure, and high NIHSS score.
| S-EPMC6124481 | biostudies-literature
Project description:Background: The mechanism of obesity paradox in stroke is not clear. This study aimed to investigate whether uric acid (UA) contributes to obesity-stroke outcome paradox. Material and Methods: The study cohort consisted of 1,984 IS patients recruited in the ACROSS-China study. Serum UA and BMI were measured at admission. Low and high BMI groups were defined by the threshold of 24, and low and high UA by the age- and sex-specific median. Poor outcomes were defined as modified Rankin scale score ?3 in 1 year after onset. Results: UA was significantly and positively correlated with BMI. Lower levels of UA and BMI were significantly associated with higher risk of poor outcomes. Incidence of the poor outcome was 34.5, 29.4, 27.7, and 23.5% in the BMI/UA groups of low/low, high/low, low/high and high/high, respectively, with p = 0.001 for trend. The association between low UA and poor outcome was significant in lower BMI groups (odds ratio = 1.36, p = 0.006 in quartile 1 and 1.28, p = 0.021 in quartile 2), but the odds ratios were not significant in the BMI quartile 3 and 4 groups, with p = 0.038 for trend. The adverse effect of lower UA was significant in males, but not in females, with p = 0.006 for sex difference. Conclusions: These findings suggest that low UA and low BMI have a joint effect on poor outcomes in IS patients. Across BMI categories, uric acid is differentially associated with functional outcome after stroke. This effect of low UA in the low BMI groups may be one of the mechanisms underlying the obesity-stroke paradox of the outcome in IS patients.
| S-EPMC6906190 | biostudies-literature