Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

A common gene variant of human extracellular superoxide dismutase (ecSOD), in ∼5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSODR213G) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSODR213G, or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 ± 4% relaxation, means ± SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 ± 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 ± 0.2 to 0.9 ± 0.2 relative light units per second per millimeter squared (RLU·s−1·mm−2)] and peroxynitrite (from 2.4 ± 0.2 to 0.9 ± 0.1 RLU·s−1·mm−2) in the aorta from rats with heart failure. Gene transfer of ecSODR213G produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSODR213G in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSODR213G in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSODR213G.

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Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00108.2005 ◽

2005 ◽

Vol 289 (2) ◽

pp. H525-H532 ◽

Cited By ~ 34

Author(s):

Shinichiro Iida ◽

Yi Chu ◽

Joseph Francis ◽

Robert M. Weiss ◽

Carol A. Gunnett ◽

...

Keyword(s):

Heart Failure ◽

Superoxide Dismutase ◽

Risk Factor ◽

Endothelial Dysfunction ◽

Gene Transfer ◽

Endothelial Function ◽

Mesenteric Artery ◽

Extracellular Superoxide Dismutase ◽

Protective Effects ◽

Sod Activity

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODΔHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODΔHBD. Gene transfer of ecSOD, but not ecSODΔHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.

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VASCULAR EFFECTS OF A GENE VARIANT OF EXTRACELLULAR SUPEROXIDE DISMUTASE IN SPONTANEOUSLY HYPERTENSIVE RATS

Cardiovascular Pathology ◽

10.1016/j.carpath.2004.03.431 ◽

2004 ◽

Vol 13 (3) ◽

pp. 143-144

Author(s):

Abdullah Alwahdani ◽

Yi Chu ◽

Robert M Brooks ◽

Donald D Lund ◽

Frank M Faraci ◽

...

Keyword(s):

Superoxide Dismutase ◽

Spontaneously Hypertensive Rats ◽

Extracellular Superoxide Dismutase ◽

Gene Variant ◽

Hypertensive Rats ◽

Vascular Effects ◽

Spontaneously Hypertensive

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Enhanced Skeletal Muscle Expression of Extracellular Superoxide Dismutase Mitigates Streptozotocin-Induced Diabetic Cardiomyopathy by Reducing Oxidative Stress and Aberrant Cell Signaling

Circulation Heart Failure ◽

10.1161/circheartfailure.114.001540 ◽

2015 ◽

Vol 8 (1) ◽

pp. 188-197 ◽

Cited By ~ 19

Author(s):

Jarrod A. Call ◽

Kristopher H. Chain ◽

Kyle S. Martin ◽

Vitor A. Lira ◽

Mitsuharu Okutsu ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Superoxide Dismutase ◽

Cell Signaling ◽

Diabetic Cardiomyopathy ◽

Extracellular Superoxide Dismutase ◽

Aberrant Cell

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

Biomedicines ◽

10.3390/biomedicines9111645 ◽

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.

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Cardiomyopathy, oxidative stress and impaired contractility in a rheumatoid arthritis mouse model

Heart ◽

10.1136/heartjnl-2018-312979 ◽

2018 ◽

Vol 104 (24) ◽

pp. 2026-2034 ◽

Cited By ~ 10

Author(s):

Gianluigi Pironti ◽

Alex Bersellini-Farinotti ◽

Nilesh M Agalave ◽

Katalin Sandor ◽

Teresa Fernandez-Zafra ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Heart Failure ◽

Mouse Model ◽

Posttranslational Modifications ◽

Contractile Function ◽

Joint Inflammation ◽

Left Ventricular ◽

Increased Risk ◽

Fractional Shortening

ObjectivesPatients with rheumatoid arthritis (RA) display an increased risk of heart failure independent of traditional cardiovascular risk factors. To elucidate myocardial disease in RA, we have investigated molecular and cellular remodelling of the heart in an established mouse model of RA.MethodsThe collagen antibody-induced arthritis (CAIA) RA mouse model is characterised by joint inflammation and increased inflammatory markers in the serum. We used CAIA mice in the postinflammatory phase that resembles medically controlled RA or RA in remission. Hearts were collected for cardiomyocyte isolation, biochemistry and histology analysis.ResultsHearts from mice subjected to CAIA displayed hypertrophy (heart/body weight, mean±SD: 5.9±0.8vs 5.1±0.7 mg/g, p<0.05), fibrosis and reduced left ventricular fractional shortening compared with control. Cardiomyocytes from CAIA mice showed reduced cytosolic [Ca2+]i transient amplitudes (F/F0, mean±SD: 3.0±1.2vs 3.6±1.5, p<0.05) that was linked to reductions in sarcoplasmic reticulum (SR) Ca2+ store (F/F0, mean±SD: 3.5±1.3vs 4.4±1.3, p<0.01) measured with Ca2+ imaging. This was associated to lower fractional shortening in the cardiomyocytes from the CAIA mice (%FS, mean±SD: 3.4±2.2 vs 4.6%±2.3%, p<0.05). Ca2+ handling proteins displayed oxidation-dependent posttranslational modifications that together with an increase in superoxide dismutase expression indicate a cell environment with oxidative stress.ConclusionsThis study shows that inflammation during active RA has long-term consequences on molecular remodelling and contractile function of the heart, which further supports that rheumatology patients should be followed for development of heart failure.

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Abstract 12954: Impairment of the Compensatory Natriuretic Peptide Response to Myocardial Infarction in the Aged is Associated With Adverse Cardiorenal Repair and Heart Failure

Circulation ◽

10.1161/circ.130.suppl_2.12954 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

S. J Sangaralingham ◽

Tomoko Ichiki ◽

Gerald E Harders ◽

Horng H Chen ◽

John C Burnett

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Natriuretic Peptide ◽

The Elderly ◽

Significant Loss ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Aged Rat ◽

Clinical Model ◽

Increased Risk

Introduction: The incidence of post-myocardial infarction (MI) heart failure (HF) is increasing in the elderly. Studies have demonstrated that B-type natriuretic peptide (BNP) mediates critical cardiorenal compensatory and protective actions through guanylyl cyclase receptor A and cGMP activation. Such actions include natriuresis, diuresis and suppression of adverse cardiorenal remodelling. Hypothesis: While the mechanism of this increased risk may be multifactorial, we hypothesized that an impairment of the compensatory protective BNP/cGMP axis in both the aged kidney and heart contributes to post-MI HF. Methods: 20 month old Fischer rats were randomized into two groups: Sham-operated (S) and MI(produced by left coronary artery ligation). Cardiorenal structure and function were assessed at 4 weeks and included mean arterial pressure(MAP), LV EF, LV chamber dimension, proteinuria, sodium (Na) excretion and fibrosis by picrosirius red staining. Plasma BNP and cGMP levels were assessed by RIA. Data presented as mean±SE,*P<0.05. Results: LV EF (S:78±2, MI:46±3 %*) was significantly reduced in aged MI rats, despite no difference in LV fibrosis in the remote region and no change in MAP compared to aged sham rats. Post-MI HF was evident and characterized by a significant reduction in Na excretion (S:0.20±0.03, MI:0.13±0.01 mEq/day*) as well as significant increases in LV dilatation (S:7.2±0.1, MI:8.3±0.2 mm*) and cardiac hypertrophy (S:2.78±0.06, MI:3.25±0.16 mg/g*) in aged MI rats. Notably, plasma BNP (S:9±1, MI:11±2 pg/ml) failed to increase and plasma cGMP (S:44±6, MI:27±3 mm*) was significantly reduced in the MI group. Importantly, MI in the aged rat resulted in a significant loss in total renal mass (S:2739±83, MI:2351±68 mg*), consistent with renal atrophy, while no changes in proteinuria or renal fibrosis were observed. Conclusions: Post-MI dysfunction of the protective BNP/cGMP axis in the aged rat was associated with various cardiorenal abnormalities including renal atrophy, which may contribute to the pathophysiology of HF. This pre-clinical model provides new insights into post-MI HF and may be used to examine therapeutic strategies using natriuretic peptides to protect the heart and kidney in the elderly post-MI population.

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Malondialdehyde and Uric Acid as Predictors of Adverse Outcome in Patients with Chronic Heart Failure

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9246138 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Ewa Romuk ◽

Celina Wojciechowska ◽

Wojciech Jacheć ◽

Aleksandra Zemła-Woszek ◽

Alina Momot ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Uric Acid ◽

Chronic Heart Failure ◽

Predictive Biomarkers ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Increased Risk ◽

Baseline Levels

In chronic heart failure (HF), some parameters of oxidative stress are correlated with disease severity. The aim of this study was to evaluate the importance of oxidative stress biomarkers in prognostic risk stratification (death and combined endpoint: heart transplantation or death). In 774 patients, aged 48-59 years, with chronic HF with reduced ejection fraction (median: 24.0 (20-29)%), parameters such as total antioxidant capacity, total oxidant status, oxidative stress index, and concentration of uric acid (UA), bilirubin, protein sulfhydryl groups (PSH), and malondialdehyde (MDA) were measured. The parameters were assessed as predictive biomarkers of mortality and combined endpoint in a 1-year follow-up. The multivariate Cox regression analysis was adjusted for other important clinical and laboratory prognostic markers. Among all the oxidative stress markers examined in multivariate analysis, only MDA and UA were found to be independent predictors of death and combined endpoint. Higher serum MDA concentration increased the risk of death by 103.0% (HR=2.103; 95% CI (1.330-3.325)) and of combined endpoint occurrence by 100% (HR=2.000; 95% CI (1.366-2.928)) per μmol/L. Baseline levels of MDA in the 4th quartile were associated with an increased risk of death with a relative risk (RR) of 3.64 (95% CI (1.917 to 6.926), p<0.001) and RR of 2.71 (95% CI (1.551 to 4.739), p<0.001) for the occurrence of combined endpoint as compared to levels of MDA in the 1st quartile. Higher serum UA concentration increased the risk of death by 2.1% (HR=1.021; 95% CI (1.005-1.038), p<0.001) and increased combined endpoint occurrence by 1.4% (HR=1.014; 95% CI (1.005-1.028), p<0.001), for every 10 μmol/L. Baseline levels of UA in the 4th quartile were associated with an increased risk for death with a RR of 3.21 (95% CI (1.734 to 5.931)) and RR of 2.73 (95% CI (1.560 to 4.766)) for the occurrence of combined endpoint as compared to the levels of UA in the 1st quartile. In patients with chronic HF, increased MDA and UA concentrations were independently related to poor prognosis in a 1-year follow-up.

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