Abstract 2609: Mitochondrial Oxidative Stress Promotes Failure of the Pressure-Loaded Infant Right Ventricle

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Huamei He ◽  
Dimitrios N Poutias ◽  
Kazuo Kitahori ◽  
Mistuhiro Kawata ◽  
Patrick Campbell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex I ◽  
Contractile Function ◽  
High Energy ◽  
Protein Carbonyl ◽  
Protein Damage ◽  
Protein Carbonyls ◽  
High Energy Phosphates ◽  
Ros Scavenging ◽  
Pressure Load

Background: Right ventricular hypertrophy (RVH) and failure induced by chronic RV pressure overload is a major problem in congenital heart disease. We have previously shown that mitochondrial (Mito) damage accompanied load-induced infant RV failure. Here we assessed Mito electron transport chain(ETC) dysfunction and Mito oxidative stress in the transition of infant RVH to failure. Methods : Newborn rabbits underwent pulmonary artery banding (or sham) causing stable RV pressure load (~40 mmHg) and RVH by 2 weeks; RV contractile function (echocardiography) was preserved for ~4 weeks, followed by failure onset at ~8 weeks. Thus, RV free wall was assayed at 3, 4 and 8 weeks for ETC enzyme activities, high energy phosphates, Mito GSH/GSSH ratio (index of Mito ROS scavenging) , Mito 8-hydroxy-2-deoxyguanosine (8-OHdG, oxidative Mito DNA damage), Mito protein carbonyls (oxidative Mito protein damage) and Mito ultrastructure (electron microscopy). Results: By 4 weeks (RVH, preserved function), Mito 8-OHdG and protein carbonyl markedly increased, accompanied by decreased complex I and III activity. At 8 weeks (early failure), there were further increases in Mito 8-OHdG and protein carbonyls, significantly decreased GSH/GSSG ratio, further loss of complex I and III, and decreased activities of complexes IV and V; ATP content and ATP/ADP ratio were also significantly reduced. In parallel the number of abnormal disrupted RV mitochondria increased markedly. Conclusion: Pressure-load of the infant RV rapidly induces Mito oxidative stress. Due to the limited Mito scavenging and repair systems, this results in a cycle of Mito DNA and protein damage, progressive loss of ETC enzyme activity and further oxidative stress, as well as loss of functional mitochondria. This load-induced oxidative stress may be a therapeutic target to preserve RV function and oxidative metabolism and prevent the transition of RVH to RV failure. Changes in banded and sham-operated hearts after surgery

scholarly journals Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure

2016 ◽  
Vol 310 (6) ◽  
pp. H667-H680 ◽  
Author(s):  
Dale J. Hamilton ◽  
Aijun Zhang ◽  
Shumin Li ◽  
Tram N. Cao ◽  
Jessie A. Smith ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Methyl Ester ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Complex I ◽  
Contractile Function ◽  
Protein Carbonyls ◽  
Energy Deprivation

Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l- NG-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.

scholarly journals Oxidative protein damage is associated with poor grip strength among older women living in the community

2007 ◽  
Vol 103 (1) ◽  
pp. 17-20 ◽  
Author(s):  
Caitlin Howard ◽  
Luigi Ferrucci ◽  
Kai Sun ◽  
Linda P. Fried ◽  
Jeremy Walston ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Older Adults ◽  
Muscle Strength ◽  
Grip Strength ◽  
Older Women ◽  
Protein Carbonyl ◽  
Protein Damage ◽  
Protein Carbonyls ◽  
Cross Sectional ◽  
Oxidative Protein Damage

Grip strength, an indicator of muscle strength, has been shown to be a predictor of poor outcomes among older adults. Protein carbonylation, an indicator of oxidative damage to proteins, leads to cellular dysfunction and a decline in tissue function. Oxidative stress has been implicated in the pathogenesis of sarcopenia. The objective was to determine whether serum protein carbonyl concentrations are associated with grip strength in older women living in the community. A cross-sectional study was conducted in 672 women, aged 65 and older, from the Women's Health and Aging Study (WHAS) I, the one-third most disabled women residing in the community in Baltimore, MD. Protein carbonyl and grip strength were measured in each patient. In a multivariate analysis adjusting for age, race, body mass index, and Mini-Mental Status Examination score, protein carbonyls (nmol/mg) were associated with grip strength (β = −6.77, P < 0.01). The statistical association was unchanged after the analysis adjusted for hypertension, congestive heart failure, and depression. Ordered logistic regression models adjusted for the above factors showed that protein carbonyls are associated with increased odds of being in the lower quartiles of grip strength (odds ratio 8.74, 95% confidence interval 1.06–71.89, P = 0.043). These results suggest oxidative protein damage is independently associated with low grip strength among older women living in the community. Increased oxidative stress may be contributing to loss of muscle strength in older adults.

scholarly journals Protein carbonyls and protein thiols in rheumatoid arthritis

2018 ◽  
Vol 6 (5) ◽  
pp. 1738 ◽  
Author(s):  
Pullaiah P. ◽  
Suchitra M. M. ◽  
Siddhartha Kumar B.
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Protein Modification ◽  
Antioxidant Properties ◽  
Protein Carbonyl ◽  
Protein Carbonyls ◽  
Carbonyl Content ◽  
Protein Thiol ◽  
Protein Carbonyl Content ◽  
Protein Thiols

Background: Oxidative stress (OS) has an important role in the pathogenesis and progression of rheumatoid arthritis (RA). OS causes protein modification, thereby impairing the biological functions of the protein. This study was conducted to assess the oxidatively modified protein as protein carbonyl content and the antioxidant status as protein thiols, and to study the association between protein carbonyls and protein thiols in RA.Methods: Newly diagnosed RA patients who were not taking any disease modifying anti-rheumatic drugs were included into the study group (n=45) along with age and sex matched healthy controls (n=45). Serum protein carbonyl content and protein thiols were estimated.Results: Elevated protein carbonyl content and decreased protein thiol levels (p<0.001) were observed in RA. A significant negative correlation was observed between protein carbonyl content and protein thiol levels (p<0.001).Conclusions: Oxidative stress in RA is evidenced by enhanced protein oxidation and decreased antioxidant protein thiol levels. Decreased protein thiols may also reflect protein modifications leading to compromise in the antioxidant properties. This oxidant and antioxidant imbalance needs to be addressed by therapeutic interventions to prevent disease progression.

Influence of intracellular acidosis on contractile function in the working rat heart

1987 ◽  
Vol 253 (6) ◽  
pp. H1499-H1505 ◽  
Author(s):  
F. M. Jeffrey ◽  
C. R. Malloy ◽  
G. K. Radda
Keyword(s):  
Stroke Volume ◽  
Intracellular Ph ◽  
Rat Heart ◽  
Contractile Function ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
Tension Development ◽  
O2 Delivery

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm

2005 ◽  
Vol 98 (5) ◽  
pp. 1753-1760 ◽  
Author(s):  
V. P. Wright ◽  
P. F. Klawitter ◽  
D. F. Iscru ◽  
A. J. Merola ◽  
T. L. Clanton
Keyword(s):  
Contractile Function ◽  
Force Production ◽  
Creatine Phosphate ◽  
High Energy ◽  
Diaphragm Muscle ◽  
Severe Hypoxia ◽  
High Energy Phosphates ◽  
Rat Diaphragm ◽  
Tetanic Force ◽  
Hypoxia Exposure

Acute exposure to severe hypoxia depresses contractile function and induces adaptations in skeletal muscle that are only partially understood. Previous studies have demonstrated that antioxidants (AOXs) given during hypoxia partially protect contractile function, but this has not been a universal finding. This study confirms that specific AOXs, known to act primarily as superoxide scavengers, protect contractile function in severe hypoxia. Furthermore, the hypothesis is tested that the mechanism of protection involves preservation of high-energy phosphates (ATP, creatine phosphate) and reductions of Pi. Rat diaphragm muscle strips were treated with AOXs and subjected to 30 min of hypoxia. Contractile function was examined by using twitch and tetanic stimulations and the degree of elevation in passive force occurring during hypoxia (contracture). High-energy phosphates were measured at the end of 30-min hypoxia exposure. Treatment with the superoxide scavengers 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron, 10 mM) or Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (50 μM) suppressed contracture during hypoxia and protected maximum tetanic force. N-acetylcysteine (10 or 18 mM) had no influence on tetanic force production. Contracture during hypoxia without AOXs was also shown to be dependent on the extracellular Ca2+ concentration. Although hypoxia resulted in only small reductions in ATP concentration, creatine phosphate concentration was decreased to ∼10% of control. There were no consistent influences of the AOX treatments on high-energy phosphates during hypoxia. The results demonstrate that superoxide scavengers can protect contractile function and reduce contracture in hypoxia through a mechanism that does not involve preservation of high-energy phosphates.

Contractile and metabolic effects of increased creatine kinase activity in mouse skeletal muscle

1996 ◽  
Vol 270 (4) ◽  
pp. C1236-C1245 ◽  
Author(s):  
B. B. Roman ◽  
J. M. Foley ◽  
R. A. Meyer ◽  
A. P. Koretsky
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Kinase Activity ◽  
Contractile Function ◽  
Contractile Activity ◽  
High Energy ◽  
Metabolic Effects ◽  
High Energy Phosphates ◽  
Lactate Dehydrogenase Activity ◽  
B Subunit

The effects of increased expression of creatine kinase (CK) in skeletal muscle were studied in control and transgenic animals homozygous for expression of the B subunit of CK. CK activity was 47% higher in transgenic gastrocnemius muscle. The CK activity was distributed as follows: 45 +/- 1% MM dinner, 31 +/- 4% MB dimer, and 22 +/- 5% BB dimer. No significant differences in metabolic or contractile proteins were detected except for a 22% decrease in lactate dehydrogenase activity and a 9% decrease in adenylate kinase activity. The only significant effect in contractile activity was that the rise time of a 5-s isometric contraction was 28% faster in the transgenic muscle. 31P nuclear magnetic resonance (NMR) spectra were obtained from control and transgenic muscles during mechanical activation, and there were no NMR measurable differences detected. These results indicate that a 50% increase in CK activity due to expression of the B subunit does not have large effects on skeletal muscle metabolism or contractile function. Therefore, control muscle has sufficient CK activity to keep up with changes in cellular high-energy phosphates except during the early phase of intense contractile activity.

Pyruvate-fortified cardioplegia suppresses oxidative stress and enhances phosphorylation potential of arrested myocardium

2005 ◽  
Vol 289 (3) ◽  
pp. H1123-H1130 ◽  
Author(s):  
E. Marty Knott ◽  
Myoung-Gwi Ryou ◽  
Jie Sun ◽  
Abraham Heymann ◽  
Arti B. Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Redox State ◽  
Energy State ◽  
High Energy ◽  
High Energy Phosphates ◽  
Cardioplegic Arrest ◽  
Phosphorylation Potential ◽  
Lactate And Pyruvate ◽  
Postischemic Myocardium

Cardioplegic arrest for bypass surgery imposes global ischemia on the myocardium, which generates oxyradicals and depletes myocardial high-energy phosphates. The glycolytic metabolite pyruvate, but not its reduced congener lactate, increases phosphorylation potential and detoxifies oxyradicals in ischemic and postischemic myocardium. This study tested the hypothesis that pyruvate mitigates oxidative stress and preserves the energy state in cardioplegically arrested myocardium. In situ swine hearts were arrested for 60 min with a 4:1 mixture of blood and crystalloid cardioplegia solution containing 188 mM glucose alone (control) or with additional 23.8 mM lactate or 23.8 mM pyruvate and then reperfused for 3 min with cardioplegia-free blood. Glutathione (GSH), glutathione disulfide (GSSG), and energy metabolites [phosphocreatine (PCr), creatine (Cr), Pi] were measured in myocardium, which was snap frozen at 45 min arrest and 3 min reperfusion to determine antioxidant GSH redox state (GSH/GSSG) and PCr phosphorylation potential {[PCr]/([Cr][Pi])}. Coronary sinus 8-isoprostane indexed oxidative stress. Pyruvate cardioplegia lowered 8-isoprostane release ∼40% during arrest versus control and lactate cardioplegia. Lactate and pyruvate cardioplegia dampened ( P < 0.05 vs. control) the surge of 8-isoprostane release following reperfusion. Pyruvate doubled GSH/GSSG versus lactate cardioplegia during arrest, but GSH/GSSG fell in all three groups after reperfusion. Myocardial [PCr]/([Cr][Pi]) was maintained in all three groups during arrest. Pyruvate cardioplegia doubled [PCr]/([Cr][Pi]) versus control and lactate cardioplegia after reperfusion. Pyruvate cardioplegia mitigates oxidative stress during cardioplegic arrest and enhances myocardial energy state on reperfusion.

scholarly journals Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics

2022 ◽  
Vol 12 ◽  
Author(s):  
Kerstin N. Timm ◽  
Vicky Ball ◽  
Jack J. Miller ◽  
Dragana Savic ◽  
James A. West ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbohydrate Metabolism ◽  
Liver Damage ◽  
Functional Decline ◽  
High Energy ◽  
Metabolic Effects ◽  
Resonance Spectroscopy ◽  
Acid Uptake ◽  
High Energy Phosphates ◽  
Time Point

Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg–1 week–1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.

Oxidative stress as a mechanism of combined OTA and CTN toxicity in rat plasma, liver and kidney

2018 ◽  
Vol 38 (4) ◽  
pp. 434-445 ◽  
Author(s):  
D Rašić ◽  
V Micek ◽  
MS Klarić ◽  
M Peraica
Keyword(s):  
Oxidative Stress ◽  
Rat Plasma ◽  
Protein Carbonyl ◽  
Protein Carbonyls ◽  
Lower Plasma ◽  
Sod Activity ◽  
Male Wistar Rats ◽  
Liver And Kidney ◽  
Gpx Activity

Ochratoxin A (OTA) and citrinin (CTN) commonly coexist in grains. Aiming to evaluate oxidative stress in OTA + CTN toxicity, male Wistar rats were orally treated with two doses of OTA (0.125 and 0.250 mg kg−1 of body weight (b.w.)), CTN (2 mg kg−1 of b.w.) and resveratrol (RSV; 20 mg kg−1 of b.w.) and combined daily during 3 weeks. Protein carbonyl concentrations were measured in kidneys and liver; catalytic activity of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) level in plasma, kidneys and liver, while malondialdehyde (MDA) concentration was measured in plasma, kidneys, liver and urine. Mycotoxin treatment significantly increased MDA concentration in plasma and kidney and decreased SOD activity in the liver. Rats treated with CTN and OTA125 + CTN had lower plasma GPx activity. Concentration of GSH in the kidney and protein carbonyls in the kidney and liver as well as GPx activity in the kidney and liver, SOD activity in the kidney and CAT activity in the liver were not affected. Protective effect of RSV was observed on GSH in the kidney and plasma and MDA in the kidney, plasma and urine. Oxidative stress is involved in OTA + CTN toxicity in vivo because such treatment affects parameters of oxidative stress, particularly in plasma. RSV can reduce but not overcome oxidative stress induced by combined OTA and CTN treatment.

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