Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that oxidative stress can regulate extracellular matrix in cardiac fibroblasts. Neonatal and adult rat cardiac fibroblasts in vitro were exposed to H(2)O(2) (0.05-5 microM) or the superoxide-generating system xanthine (500 microM) plus xanthine oxidase (0.001-0.1 mU/ml) (XXO) for 24 h. In-gel zymography demonstrated that H(2)O(2) and XXO each increased gelatinase activity corresponding to matrix metalloproteinases (MMP) MMP-13, MMP-2, and MMP-9. H(2)O(2) and XXO decreased collagen synthesis (collagenase-sensitive [(3)H]proline incorporation) without affecting total protein synthesis ([(3)H]leucine incorporation). H(2)O(2) and XXO decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha(1)(III) mRNA but increased the expression of fibronectin mRNA, suggesting a selective transcriptional effect on collagen synthesis. H(2)O(2), but not XXO, also decreased the expression of nonfibrillar procollagen alpha(1)(IV) and alpha(2)(IV) mRNA. To determine the role of endogenous antioxidant systems, cells were treated with the superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DDC, 100 microM) to increase intracellular superoxide or with the glucose-6-phosphate dehydrogenase inhibitor dehydroisoandrosterone 3-acetate (DHEA; 10 microM) to increase intracellular H(2)O(2). DDC and DHEA decreased collagen synthesis and increased MMP activity, and both effects were inhibited by an SOD/catalase mimetic. Thus increased oxidative stress activates MMPs and decreases fibrillar collagen synthesis in cardiac fibroblasts. Oxidative stress may play a role in the pathogenesis of myocardial remodeling by regulating the quantity and quality of extracellular matrix.
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PMID:Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. 1112 76

Many clinical and experimental studies have established the beneficial effect of kinins in hypertension, heart failure and ischaemia-reperfusion syndrome, but little attention has been given to the role of kinins in hyperglycaemic conditions. The purpose of the present study was to determine the influence of bradykinin on the levels of glucose, insulin, malondialdehyde and hydrogen peroxide, as well as antioxidative enzyme activity in rats with streptozotocin (STZ)-induced acute hyperglycaemia. In STZ-induced hyperglycaemic rats the levels of glucose, hydrogen peroxide and malondialdehyde were increased by 256% (from 6.0+/-0.3 to 21.4+/-1.3 mmol/l, P<0.001), 33% (from 1.9+/-0.1 to 5.6+/-0.3 mmol H(2)O(2)/ml, P<0.001) and 19% (from 3.7+/-0.3 to 4.9+/-0.2 nmol/l, P<0.001) respectively. The activity of superoxide dismutase, catalase and glutathione peroxidase and the level of insulin were decreased by 46% (from 1367+/-73 to 737+/-59 U/g Hb, P<0.001), 36% (from 2.3+/-0.3 to 1.4+/-0.1 U Bergmayera/g Hb, P<0.001), 31% (from 236+/-19 to 163+/-24 U/g Hb, P<0.001) and 91% (from 47.5+/-1.7 to 2.4+/-0.5 mU/l, P<0.001) respectively in rats treated with streptozotocin. The administration of bradykinin caused the decrease in glucose, hydrogen peroxide and malondi-aldehyde levels by 38% (from 21.4+/-1.3 to 13.3+/-1.0 mmol/l, P<0.001), 37% (from 5.6+/-0.3 to 4.3+/-0.2 mmol H2O2/ml, P<0.001), 39% (from 4.9+/-0.2 to 3.0+/-0.2 nmol/l, P<0.001) respectively and the increase in insulin level and superoxide dismutase, catalase and glutathione peroxidase activity by 62% (from 2.4+/-0.5 to 4.0+/-0.4 mU/l, P<0.001), 23% (from 736.8+/-58.5 to 906.7+/-47.8 U/g Hb, P<0.001), 23% (from 1.4+/-0.1 to 1.9+/-0.1 U Bergmayera/g Hb, P<0.01) and 19% (from 163.1+/-23.6 to 202.3+/-11.7 U/g Hb, P<0.001) respectively in rats with hyperglycaemia. Thus, bradykinin is able to reduce oxidative stress in hyperglycaemic conditions.
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PMID:The effect of bradykinin on the oxidative state of rats with acute hyperglycaemia. 1116 87

Patients with chronic renal and heart failure present with hypertension and widespread vasoconstriction, respectively. Although systemic release of nitric oxide (NO) may be elevated in both pathological syndromes, enhanced production of NO fails to overcome endothelial dysfunction. Plasma concentrations of L-arginine, a cationic amino acid precursor for NO synthesis, are reduced whilst levels of the endogenous L-arginine analogues, asymmetric and symmetric dimethyl arginine and N(G)-monomethyl-L-arginine, seem to be elevated. We have reported that transport of L-arginine via the cationic amino acid transporters y(+)/CAT and/or y(+)L are up-regulated in erythrocytes, peripheral blood mononuclear cells and platelets from both patients with either chronic renal or heart failure. A possible explanation why NO serves as a failing counter-regulatory mechanism in both these pathologies is that availability of L-arginine for NO production is reduced despite the observed increase in membrane transport. This review examines the mechanisms underlying alterations in NO production in chronic renal and heart failure, and the possible role of L-arginine transport in vascular and platelet dysfunction observed in both syndromes.
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PMID:Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure. 1123 Sep 69

Increased oxidative stress and antioxidant deficit have been suggested to play a major role in adriamycin-induced cardiomyopathy and congestive heart failure due to multiple treatments with adriamycin (doxorubicin). In this study, we investigated the acute effects of a single dose of adriamycin on myocardial antioxidant enzymes in rats. Adriamycin (2.5 mg/kg) was injected (i.p.) and myocardial antioxidant enzyme activities, mRNA abundance and protein levels at 1, 2, 4 and 24 h were examined. While manganese superoxide dismutase (MnSOD), glutathione peroxidase (GSHPx) and catalase (CAT) activities were not significantly changed, copper-zinc superoxide dismutase (CuZnSOD) activity was reduced at all time points and this change correlated with a decrease in its protein content. CuZnSOD mRNA was increased at 1 and 24 h. GSHPx mRNA and protein levels were transiently decreased by 20 and 25% respectively at 2 h. MnSOD mRNA was not significantly changed, but its protein levels were significantly decreased at 1 h. Lipid peroxidation was increased transiently at 1, 2 and 4 h. A transient depression in antioxidant enzyme as well as transient increase in oxidative stress with a single dose of adriamycin may precede more sustained changes seen with the repeated administration of the drug and contribute to the development of cardiomyopathy and heart failure.
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PMID:Early changes in myocardial antioxidant enzymes in rats treated with adriamycin. 1203 Mar 76

Nitric oxide (*NO) and its by-products modulate many physiological functions of skeletal muscle including blood flow, metabolism, glucose uptake, and contractile function. However, growing evidence suggests that an overproduction of nitric oxide contributes to muscle wasting in a number of pathologies including chronic heart failure, sepsis, COPD, muscular dystrophy, and extreme disuse. Limited data point to the potential of inhibition various enzymes by reactive nitrogen species (RNS), including (.)NO and its downstream products such as peroxynitrite, primarily in purified systems. We hypothesized that exposure of skeletal muscle to RNS donors would reduce or downregulate activities of the crucial antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). Diaphragm muscle fiber bundles were extracted from 4-month-old Fischer-344 rats and, in a series of experiments, exposed to either (a) 0 (control), 1, or 5 mM diethylamine NONOate (DEANO: *NO donor); (b) 0, 100, 500 microM, or 1 mM sodium nitroprusside (SNP: *NO donor); (c) 0 or 2 mM S-nitroso-acetylpenicillamine (SNAP: *NO donor); or (d) 0 or 500 microM SIN-1 (peroxynitrite donor) for 60 min. DEANO resulted in a 50% reduction in CAT, GPX, and a dose-dependent inhibition of Cu, Zn-SOD. SNP resulted in significantly lower activities for total SOD, Mn-SOD isoform, Cu, Zn-SOD isoform, CAT, and GPX in a dose-dependent fashion. Two millimolar SNAP and 500 microM SIN-1 also resulted in a large and significant inhibition of total SOD and CAT. These data indicate that reactive nitrogen species impair antioxidant enzyme function in an RNS donor-specific and dose-dependent manner and are consistent with the hypothesis that excess RNS production contributes to skeletal muscle oxidative stress and muscle dysfunction.
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PMID:Specificity of antioxidant enzyme inhibition in skeletal muscle to reactive nitrogen species donors. 1207 89

Reactive oxygen species (ROS) play a role in cardiovascular diseases such as heart failure and hypertension. Furthermore, increasing evidence has accumulated suggesting that ROS can also be formed subsequent to the stimulation of various receptors, thus functioning as second messengers. The objective of the present study was to elucidate the role of intracellular-generated ROS in the inotropic and chronotropic effects of the alpha1- and beta-adrenoceptor and the ET-receptor stimulation in isolated rat atria. In addition, we investigated whether the MAPKerk pathway is involved in the ROS-provoked rise of contractile force. For this purpose hydrogen peroxide was applied, which is known to serve several endogenous functions as a second messenger. Moreover, hydrogen peroxide readily crosses cell membranes, which thus allows to mimic the intracellular formation. Preincubation of atria with EUK 8 (400 microM), a cell permeable superoxide dismutase- and catalase-mimetic, reduced the positive inotropic effect upon alpha1-adrenoceptor and ET-receptor stimulation. The responsiveness to beta-adrenoceptor stimulation remained unaffected by this pretreatment. The chronotropic effects were not altered by preincubation with EUK 8. In contrast to the MAPK(p38) inhibitor SB203580 (2 and 10 microM), the two MKKmek inhibitors PD98059 (30 and 100 microM) and U0126 (10 microM) significantly attenuated the positive inotropic response to hydrogen peroxide in isolated rat left atria. In addition, inhibition of the Na+/H+ exchange (NHE) by cariporide (1 microM) counteracted ROS-provoked increase of contractile force. From the present study we conclude that the inotropic responses to alpha1-adrenoceptor and ET-receptor stimulation are, at least partially, caused by intracellular-formed ROS, that subsequently may activate the MAPKerk pathway and the NHE.
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PMID:The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation. 1273 26

Skeletal muscle disuse with space-flight and ground-based models (e.g., hindlimb unloading) results in dramatic skeletal muscle atrophy and weakness. Pathological conditions that cause muscle wasting (i.e., heart failure, muscular dystrophy, sepsis, COPD, cancer) are characterized by elevated "oxidative stress," where antioxidant defenses are overwhelmed by oxidant production. However, the existence, cellular mechanisms, and ramifications of oxidative stress in skeletal muscle subjected to hindlimb unloading are poorly understood. Thus we examined the effects of hindlimb unloading on hindlimb muscle antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase), nonenzymatic antioxidant scavenging capacity (ASC), total hydroperoxides, and dichlorohydrofluorescein diacetate (DCFH-DA) oxidation, a direct indicator of oxidative stress. Twelve 6 month old Sprague Dawley rats were divided into two groups: 28 d of hindlimb unloading (n = 6) and controls (n = 6). Hindlimb unloading resulted in a small decrease in Mn-superoxide dismutase activity (10.1%) in the soleus muscle, while Cu,Zn-superoxide dismutase increased 71.2%. In contrast, catalase and glutathione peroxidase, antioxidant enzymes that remove hydroperoxides, were significantly reduced in the soleus with hindlimb unloading by 54.5 and 16.1%, respectively. Hindlimb unloading also significantly reduced ASC. Hindlimb unloading increased soleus lipid hydroperoxide levels by 21.6% and hindlimb muscle DCFH-DA oxidation by 162.1%. These results indicate that hindlimb unloading results in a disruption of antioxidant status, elevation of hydroperoxides, and an increase in oxidative stress.
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PMID:Hindlimb unloading increases oxidative stress and disrupts antioxidant capacity in skeletal muscle. 1282 51

In the left ventricle subjected to pressure overload activity, the antioxidant enzymes increased at the hyperfunctional stage. During the transition to heart failure, these enzymes are down-regulated, oxidative stress increases, and apoptosis progresses. Maladaptative activation of the antioxidant enzymes at an early stage may contribute to the intrinsic vulnerability of right ventricle to pressure overload. The authors studied changes in expression and activity of the enzymes manganese and copper-zinc superoxide dismutases, glutathione peroxidase, and catalase in the right ventricle of rat following induction of pulmonary hypertension by injection of monocrotaline. Increase in the manganese superoxide dismutase was delayed to the late failing stage, activity of glutathione peroxidase was depressed throughout, and only catalase was activated at the early stage before returning to control levels. This inability to activate antioxidant enzymes may contribute to the deleterious consequences of pressure overload on right ventricle systolic function.
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PMID:The activation pattern of the antioxidant enzymes in the right ventricle of rat in response to pressure overload is of heart failure type. 1450 27

Increased oxidative stress and reduction in antioxidant enzymes have been suggested to be involved in the pathophysiology of congestive heart failure subsequent to myocardial infarction (MI). The objective of the present study was to characterize changes in the mRNA abundance and protein levels for the enzymatic antioxidants, superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase during the sequelae of congestive heart failure in rats. MI was produced by the ligation of the left coronary artery and hearts from controls and 1, 4 and 16 week PMI groups were analyzed. Losartan treatment (2 mg/ml in drinking water, daily) was started at 4 weeks and continued for 12 weeks. The mRNA levels for SOD were reduced by about 40% at 1-week PMI, were near to the control levels at 4-week PMI and at 16 weeks PMI, the levels were reduced by about 73% below the controls. GSHPx mRNA levels remained unchanged at all time points. The mRNA levels for catalase remained unchanged at 1 and 4 weeks PMI and were significantly reduced by about 44% at 16 weeks PMI as compared to the controls. The protein levels for MnSOD, CuZnSOD, GSHPx at 1 and 16 weeks remained unchanged in treated and untreated PMI groups. However, the protein levels for catalase was significantly increased in the control and PMI groups treated with Losartan. It is concluded that changes in the SOD and catalase activities during severe heart failure correlated with changes in mRNA for these enzymes. The precise mechanism/s for the improvement in antioxidant reserve and protein levels after Losartan treatment is/are unclear at this time.
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PMID:Antioxidant enzyme gene expression in congestive heart failure following myocardial infarction. 1457 98

Primary amyloidosis is a systemic disorder characterized by the clonal production and tissue deposition of immunoglobulin light chain (LC) proteins. Congestive heart failure remains the greatest cause of death in primary amyloidosis, due to the development of a rapidly progressive amyloid cardiomyopathy. Amyloid cardiomyopathy is largely unresponsive to current heart failure therapies, and is associated with a median survival of less than 6 months and a 5-year survival of less than 10%. The mechanisms underlying this disorder, however, remain unknown. In this report, we demonstrate that physiological levels of human amyloid LC proteins, isolated from patients with amyloid cardiomyopathy (cardiac-LC), specifically alter cellular redox state in isolated cardiomyocytes, marked by an increase in intracellular reactive oxygen species and upregulation of the redox-sensitive protein, heme oxygenase-1. In contrast, vehicle or control LC proteins isolated from patients without cardiac involvement did not alter cardiomyocyte redox status. Oxidant stress imposed by cardiac-LC proteins further resulted in direct impairment of cardiomyocyte contractility and relaxation, associated with alterations in intracellular calcium handling. Cardiomyocyte dysfunction induced by cardiac-LC proteins was independent of neurohormonal stimulants, vascular factors, or extracellular fibril deposition, and was prevented through treatment with a superoxide dismutase/catalase mimetic. This study suggests that cardiac dysfunction in amyloid cardiomyopathy is directly mediated by LC protein-induced cardiomyocyte oxidant stress and alterations in cellular redox status, independent of fibril deposition. Antioxidant therapies or treatment strategies aimed at eliminating circulating LC proteins may therefore be beneficial in the treatment of this fatal disease.
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PMID:Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. 1504 25


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