scholarly journals Role of Oxidative Stress in Heart Failure: Insights from Gene Transfer Studies

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1645
Author(s):  
Bart De Geest ◽  
Mudit Mishra
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Gene Therapy ◽  
Steady State ◽  
Gene Transfer ◽  
Oxidative Modification ◽  
Heme Oxygenase 1 ◽  
Therapy Studies ◽  
Pathological Remodeling

Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sven T Pleger ◽  
Changguang Shan ◽  
Jan Kziencek ◽  
Oliver Mueller ◽  
Raffi Bekeredjian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Large Animal ◽  
Circumflex Artery ◽  
Cell Counts ◽  
Clinical Conditions

Background: Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models in vivo and in vitro via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions. Methods and Results: Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10 13 total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10 13 tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs. Conclusions: Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.

Abstract 125: Perturbation of Mitochondrial Calcium Uniporter Promotes Cardiac Oxidative Stress and Autophagy During Heart Failure

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sudarsan Rajan ◽  
Santhanam Shanmughapriya ◽  
Dhanendra Tomar ◽  
Zhiwei Dong ◽  
Joseph Y Cheung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Mouse Model ◽  
Atp Depletion ◽  
Regulatory Role ◽  
Mitochondrial Calcium ◽  
Mitochondrial Bioenergetics ◽  
Complex Assembly ◽  
New Findings

Mitochondrial calcium ([Ca 2+ ] m ) is essential for cardiomyocyte viability, and aberration of [Ca 2+ ] m is known to elicit multiple cardiac stress conditions associated with ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening, all of which can lead to metabolic stress and the loss of dysfunctional mitochondria by aberrant autophagy. Elucidating the regulatory role of m itochondrial c alcium u niporter (MCU)-mediated [Ca 2+ ] m in modulating cardiac mitochondrial bioenergetics and autophagy has high significance and clinical impact for many pathophysiological processes. [Ca 2+ ] m is exquisitely controlled by the inner mitochondrial membrane uniporter, transporters, regulators and exchangers including MCU, MCUR1, EMRE, MICU1, MICU2 and LETM1. Our recently published findings revealed that Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) serves as a scaffold factor for uniporter complex assembly. We found that deletion of MCUR1 impaired [Ca 2+ ] m uptake, mitochondrial Ca 2+ current ( I MCU ) and mitochondrial bioenergetics and is associated with increased autophagy. Our new findings indicate that the impairment of [Ca 2+ ] m uptake exacerbated autophagy following ischemia-reperfusion (I/R) injury. In support of our mouse model, human failing hearts show that MCUR1 protein levels are markedly decreased and autophagy markers are increased, demonstrating a crucial link between [Ca 2+ ] m uptake and autophagy during heart failure. Additionally, our results reveal that either oxidation or disruption of human MCU Cys-97 (in mouse Cys-96; gain-of-function MCU C96A mutant) produces a conformational change within the N terminal β-grasp fold of MCU which promotes higher-order MCU complex assembly and increased I MCU activity and mitochondrial ROS levels. The results of our studies using a novel cardiac-specific MCUR1-KO model and a constitutively active global MCU C96A KI mouse model (CRISPR-Cas9 genome edited) elucidate the regulatory role of [Ca 2+ ] m in cardiac bioenergetics and autophagy during oxidative stress and myocardial infarction. Thus, targeting assembly and the activity of MCU complex will offer a new potential therapeutic target in the treatment of cardiomyopathy and heart failure.

Abstract 865: Gata-4 Is An Angiogenic Survival Factor Of The Infarcted Heart

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Olli Tenhunen ◽  
Hanna Leskinen ◽  
Raisa Serpi ◽  
Jaana Rysä ◽  
Harri Pennanen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Gene Transfer ◽  
Dna Binding ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Cardiac Stem Cells

Recent data suggest that the cardiac-restricted transcription factor GATA-4 is an anti-apoptotic factor required for adaptive responses as well as a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of post-infarction left ventricular remodeling represents an important target for therapeutic interventions. Here we studied the role of GATA-4 as a mediator of post-infarction remodeling. Rats were subjected to experimental myocardial infarction (MI) by ligating the left anterior descending coronary artery (LAD). Ligation of the LAD decreased the DNA binding activity of GATA-4 by 69 % at day 1 after MI (P<0.001, n=7– 8) as assessed by gel mobility shift assays. At 2 weeks the GATA-4 DNA binding was significantly upregulated (2.4-fold, P<0.05, n=7), and returned to baseline at 4 weeks. To determine the functional role of GATA-4, rats underwent LAD ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4. Hearts treated with the GATA-4 gene transfer exhibited significantly increased ejection fraction (58±5% vs. 38±3% in LacZ-treated control animals with MI, P<0.001, n=8 –9) and fractional shortening (28±3% vs. 16±1%, P<0.001, n=8 –9) 2 weeks after MI. Accordingly, the infarct size was significantly reduced (26±4% vs. 45±4%, P<0.01, n=8 –9). To determine the cardioprotective mechanisms of GATA-4, the number of cardiac stem cells, apoptotic cardiomyocytes and capillaries were assessed. The number of capillaries (59±4/field vs. 48±3/field, P<0.051, n=7– 8) and c-kit positive stem cells (13±5 cells vs. 4±2 cells, P<0.05, n=7– 8) were increased in GATA-4 treated hearts, and a tendency to decreased apoptosis was observed in TUNEL-stained histological sections. These results indicate that the reversal of reduced GATA-4 activity prevents adverse post-infarction remodeling through increased angiogenesis, recruitment of cardiac stem cells and anti-apoptosis. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.

scholarly journals Defense and protection mechanisms in lung exposed to asbestiform fiber: the role of macrophage migration inhibitory factor and heme oxygenase-1

2020 ◽  
Vol 64 (2) ◽  
Author(s):  
Carla Loreto ◽  
Rosario Caltabiano ◽  
Adriana Carol Eleonora Graziano ◽  
Sergio Castorina ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Lung Fibroblasts ◽  
Heme Oxygenase 1 ◽  
Macrophage Migration

Fluoro-edenite (FE), an asbestiform fiber, is responsible for many respiratory pathologies: chronic obstructive diseases, pleural plaques, fibrosis, and malignant mesothelioma. Macrophage migration inhibitory factor (MIF) is one of the first cytokines produced in response to lung tissue damage. Heme oxygenase-1 (HO-1) is a protein with protective effects against oxidative stress. It is up regulated by several stimuli including pro-inflammatory cytokines and factors that promote oxidative stress. In this research, the in vivo model of sheep lungs naturally exposed to FE was studied in order to shed light on the pathophysiological events sustaining exposure to fibers, by determining immunohistochemical lung expression of MIF and HO-1. Protein levels expression of HO-1 and MIF were also evaluated in human primary lung fibroblasts after exposure to FE fibers in vitro. In exposed sheep lungs, MIF and HO-1 immunoexpression were spread involving the intraparenchymal stroma around bronchioles, interstitium between alveoli, alveolar epithelium and macrophages. High MIF immunoexpression prevails in macrophages. Similar results were obtained in vitro, but significantly higher values were only detected for HO-1 at concentrations of 50 and 100 μg/mL of FE fibers. MIF and HO-1 expressions seem to play a role in lung self-protection against uncontrolled chronic inflammation, thus counteracting the strong link with cancer development, induced by exposure to FE. Further studies will be conducted in order to add more information about the role of MIF and HO-1 in the toxicity FE-induced.

scholarly journals Effect of Blueberry Anthocyanins Malvidin and Glycosides on the Antioxidant Properties in Endothelial Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Wuyang Huang ◽  
Yunming Zhu ◽  
Chunyang Li ◽  
Zhongquan Sui ◽  
Weihong Min
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Functional Food ◽  
Functional Role ◽  
Antioxidant Properties ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Good Resource

The objective of this research was to survey the antioxidant functional role of the main anthocyanins of blueberries in endothelial cells. Changes on the reactive oxygen species (ROS), xanthine oxidase-1 (XO-1), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) in cells of malvidin and the two glycosides were investigated. The results showed that these anthocyanins decreased the levels of ROS and XO-1 but increased the levels of SOD and HO-1. Glycosides improved the antioxidant capacity of malvidin to a great extent. The changes in the antioxidant properties of malvidin-3-glucoside were more pronounced than malvidin-3-galactoside. Variation in levels of malvidin-3-glucoside and malvidin-3-galactoside had a significant impact on antioxidant properties to different extents. It indicates that blueberries are a good resource of anthocyanins, which can protect cells from oxidative deterioration and use blueberry as a potential functional food to prevent diseases related to oxidative stress.

scholarly journals S-Allyl Cysteine Alleviates Hydrogen Peroxide Induced Oxidative Injury and Apoptosis through Upregulation of Akt/Nrf-2/HO-1 Signaling Pathway in HepG2 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Chitra Basu ◽  
Runa Sur
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Oxidative Damage ◽  
Hepg2 Cells ◽  
Liver Diseases ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Cell Viability Assay

Hydrogen peroxide (H2O2) mediated oxidative stress leading to hepatocyte apoptosis plays a pivotal role in the pathophysiology of several chronic liver diseases. This study demonstrates that S-allyl cysteine (SAC) renders cytoprotective effects on H2O2 induced oxidative damage and apoptosis in HepG2 cells. Cell viability assay showed that SAC protected HepG2 cells from H2O2 induced cytotoxicity. Further, SAC treatment dose dependently inhibited H2O2 induced apoptosis via decreasing the Bax/Bcl-2 ratio, restoring mitochondrial membrane potential (∆Ψm), inhibiting mitochondrial cytochrome c release, and inhibiting proteolytic cleavage of caspase-3. SAC protected cells from H2O2 induced oxidative damage by inhibiting reactive oxygen species accumulation and lipid peroxidation. The mechanism underlying the antiapoptotic and antioxidative role of SAC is the induction of the heme oxygenase-1 (HO-1) gene in an NF-E2-related factor-2 (Nrf-2) and Akt dependent manner. Specifically SAC was found to induce the phosphorylation of Akt and enhance the nuclear localization of Nrf-2 in cells. Our results were further confirmed by specific HO-1 gene knockdown studies which clearly demonstrated that HO-1 induction indeed played a key role in SAC mediated inhibition of apoptosis and ROS production in HepG2 cells, thus suggesting a hepatoprotective role of SAC in combating oxidative stress mediated liver diseases.

The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells

2005 ◽  
Vol 83 (1) ◽  
pp. 63-68 ◽  
Author(s):  
Lingyun Wu
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Mesenteric Artery ◽  
Advanced Glycation Endproducts ◽  
Muscle Cells ◽  
Heme Oxygenase 1 ◽  
Rat Mesenteric Artery ◽  
Cultured Smooth Muscle Cells

Methylglyoxal (MG), a highly reactive metabolite of glucose, causes non-enzymatic glycation of proteins to form irreversible advanced glycation endproducts (AGEs). The present study investigated whether methylglyoxal induced oxidative stress and activated nuclear factor kappa B (NF-κB) in freshly isolated and cultured smooth muscle cells (SMCs) from rat mesenteric artery. The treatment of cells with MG (50 or 100 µmol/L) induced a significant increase in AGE formation and oxidation of DCF. MG-enhanced generation of AGEs and the oxidation of DCF was markedly inhibited by antioxidant n-acetylcysteine (NAC, 600 µmol/L). MG at a concentration of 100 µmol/L increased the heme-oxygenase-1 expression in these cells. Moreover, MG activated NF-κB p65, indicated by an increased im muno cytochemistry stain for NF-κB p65 located in the nucleus after the treatment of mesenteric artery SMCs with MG. MG-induced activation of NF-κB p65 was inhibited by NAC. In summary, MG significantly increases oxidative stress and activates NF-κB p65 in mesenteric artery SMCs. The pro-oxidant role of methylglyoxal may contribute to various pathological changes of SMCs from resistance arteries.Key words: methylglyoxal, oxidative stress, NF-κB p65, vascular smooth muscle cells, mesenteric artery.

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