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)

We had reported that increased levels of endogenous ghrelin during the progression of doxorubicin-induced cardiomyopathy and heart failure might provide a compensatory self-protective effect. We investigated which pathway(s) produced these protective effects in vitro. Primary cultured cardiomyocytes were induced with doxorubicin in the presence or absence of ghrelin or a tumor necrosis factor-alpha (TNF-alpha) antagonist (etanercept). Ghrelin up-regulated TNF-alpha in a time- and dose-dependent manner. It significantly reduced cell apoptosis and markers of oxidative stress, such as malondialdehyde (MDA) content and lactate dehydrogenase (LDH) activity; it also increased anti-oxidative enzyme activity such as superoxide dismutase (MnSOD) and catalase (CAT), retained mitochondrial membrane potential and energy metabolism compared with doxorubicin alone. Moreover, ghrelin increased mitochondrial anti-apoptosis related gene protein expression such as bcl-2 and MnSOD, reduced cytoplasmic cytochrome C (Cyt C) release and strengthened the activation of NF-kappaB. All these effects were abrogated by etanercept. This suggests ghrelin affects the TNF-alpha/NF-kappaB activation pathways, up-regulating TNF-alpha, to produce anti-oxidative and anti-apoptotic effects that protected cardiomyocytes from doxorubicin-induced cytotoxicity.
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PMID:Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms. 1840 Mar 55

An increase in oxidative stress is suggested to be intimately involved in the pathogenesis of heart failure. Phenolic acids are widespread in plant foods; they contain important biological and pharmacological properties. This study evaluated the role of phenolic acids on the expression of antioxidant enzymes in the heart of male Sprague-Dawley rats. Gallic acid, ferulic acid and p-coumaric acid at a dosage of 100 mg kg(-1) body weight significantly increased the activities of cardiac superoxide dismutase, glutathione peroxidase (GPx) and catalase (CAT) as compared with control rats (P<.05). The changes in cardiac CuZnSOD, GPx and CAT mRNA levels induced by phenolic acids were similar to those noted in the enzyme activity levels. A significant (P<.05) increase in the GSH/GSSG ratio was observed in the heart of phenolic acid-treated rats. The heart homogenates obtained from rats that were administered phenolic acids displayed significant (P<.05) increases in capacity for oxygen radical absorbance compared with control rats. Immunoblot analysis revealed the increased cardiac total level of Nrf2 in phenolic acid-treated rats. Interestingly, phenolic acid-mediated antioxidant enzyme expression was accompanied by up-regulation of heme oxygenase-1. This study demonstrates that antioxidant enzymes in rat cardiac tissue can be significantly induced by phenolic acids following oral administration.
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PMID:Inducing gene expression of cardiac antioxidant enzymes by dietary phenolic acids in rats. 1854 98

We investigated the effects of an isolated soy protein (ISP) diet offered over a 9-week period to rats in whom myocardial infarction (MI) had been induced, and a casein diet given as a control. Male Wistar rats were assigned to six groups after infarct size determination (n=8/group): Sham Casein (SC); Infarct Casein <25% (IC<25%); Infarct Casein >25% (IC>25%); Sham Soy (SS); Infarct Soy <25% (IS<25%); and Infarct Soy >25% (IS>25%). MI surgery was performed at the fifth week, and one month later, the animals were hemodynamically assessed to evaluate left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), contractility and relaxation indexes (+/-dP/dt). Lung and liver specimens were also collected for the estimation of organ congestion. Oxidative stress was evaluated in heart homogenates through chemiluminescence (CL), carbonyl groups, and antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Infarcted groups treated with casein showed cardiac hypertrophy, lung and liver congestion, increased LVEDP and decreased LVSP and +/-dP/dt, all typical signals of heart failure. Ventricular dysfunction was correlated with increased myocardial oxidative damage as seen by CL and carbonyl groups data in the groups IC<25% and IC>25% (3 and 10-fold increase, respectively). The ISP diet was able to improve ventricular systolic and diastolic function in the groups IS<25% and IS>25% (LVEDP was reduced by 44% and 24%, respectively) and to decrease myocardial oxidative stress. The overall results confirm the preventive role of soy-derived products in terms of post-MI myocardial dysfunction probably by an antioxidant action.
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PMID:Diet with isolated soy protein reduces oxidative stress and preserves ventricular function in rats with myocardial infarction. 1857 92

Besides other organic nitrates, nitroglycerin (glyceryl trinitrate; GTN) has been used to treat acute heart failure particularly due to ischemic heart disease. However, one of serious clinical problems of the GTN therapy, particularly a long-standing medication, is hemodynamic tolerance to GTN, manifested by the decreased therapeutic efficacy of the drug. The most recent studies have suggested that mitochondrial lipoate/dihydrolipoate system-dependent aldehyde dehydrogenase-2 plays a key role in nitric oxide release from GTN. The aldehyde dehydrogenase-2 performs three enzymatic activities of dehydrogenase, esterase and reductase. The reductase activity is responsible for bioactivation of organic nitrates, such as GTN yielding nitrite and dinitrate (1,2-GDN/1,3-GDN, approximately 8:1). In view of a large contribution of dihydrolipoic acid to stabilization and regeneration of thiol groups, necessary for the reductase activity of aldehyde dehydrogenase-2, we conducted studies aimed to determine whether lipoic acid administration to rats is able to prevent GTN tolerance. The studies were conducted on 4 groups of animals: control saline-treated, model GTN-tolerant, GTN + lipoic acid-treated, lipoic acid alone-administered groups. On the 9th day of experiment animals were given i.v. therapeutic dose of GTN. We measured in all animals systolic and diastolic blood pressure before injection of therapeutic dose of GTN into the cadual vein and during 20 min thereafter. Levels of nitric oxide and reactive oxygen species and activities of glutathione peroxidase and superoxide dismutase were assayed in the aorta, plasma and heart of all animals. In addition, levels of malondialdehyde, and non-protein thiols, and activities of glutathione S-transferase and gamma-glutamyl transpeptidase were evaluated in the heart and plasma. The obtained results indicate that treatment of rats with a combination of lipoic acid and GTN can efficiently counteract GTN tolerance.
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PMID:The role of lipoic acid in prevention of nitroglycerin tolerance. 1861 39

Dysregulation in central nervous system (CNS) signaling that results in chronic sympathetic hyperactivity is now recognized to play a critical role in the pathogenesis of heart failure (HF) following myocardial infarction (MI). We recently demonstrated that adenovirus-mediated gene transfer of cytoplasmic superoxide dismutase (Ad-Cu/ZnSOD) to forebrain circumventricular organs, unique sensory structures that lack a blood-brain barrier and link peripheral blood-borne signals to central nervous system cardiovascular circuits, inhibits both the MI-induced activation of these central signaling pathways and the accompanying sympathoexcitation. Here, we tested the hypothesis that this forebrain-targeted reduction in oxidative stress translates into amelioration of the post-MI decline in myocardial function and increase in mortality. Adult C57BL/6 mice underwent left coronary artery ligation or sham surgery along with forebrain-targeted gene transfer of Ad-Cu/ZnSOD or a control vector. The results demonstrate marked MI-induced increases in superoxide radical formation in one of these forebrain regions, the subfornical organ (SFO). Ad-Cu/ZnSOD targeted to this region abolished the increased superoxide levels and led to significantly improved myocardial function compared with control vector-treated mice. This was accompanied by diminished levels of cardiomyocyte apoptosis in the Ad-Cu/ZnSOD but not the control vector-treated group. These effects of superoxide scavenging with Ad-Cu/ZnSOD in the forebrain paralleled increased post-MI survival rates compared with controls. This suggests that oxidative stress in the SFO plays a critical role in the deterioration of cardiac function following MI and underscores the promise of CNS-targeted antioxidant therapy for the treatment of MI-induced HF.
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PMID:Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction. 1897 55

Cardiovascular disease (CVD) remains the leading cause of morbidity and premature mortality in both women and men in most industrialized countries, and has for some time also established a prominent role in developing nations. In fact, obesity, diabetes mellitus and hypertension are now commonplace even in children and youths. Regular exercise is rapidly gaining widespread advocacy as a preventative measure in schools, medical circles and in the popular media. There is overwhelming evidence garnered from a number of sources, including epidemiological, prospective cohort and intervention studies, suggesting that CVD is largely a disease associated with physical inactivity. A rapidly advancing body of human and animal data confirms an important beneficial role for exercise in the prevention and treatment of CVD. In Part 1 of this review we discuss the impact of exercise on CVD, and we highlight the effects of exercise on (i) endothelial function by regulation of endothelial genes mediating oxidative metabolism, inflammation, apoptosis, cellular growth and proliferation, increased superoxide dismutase (SOD)-1, down-regulation of p67phox, changes in intracellular calcium level, increased vascular endothelial nitric oxide synthase (eNOS), expression and eNOS Ser-1177 phosphorylation; (ii) vascular smooth muscle function by either an increased affinity of the Ca2+ extrusion mechanism or an augmented Ca2+ buffering system by the superficial sarcoplasmic reticulum to increase Ca2+ sequestration, increase in K+ channel activity and/or expression, and increase in L-type Ca2+ current density; (iii) antioxidant systems by elevation of Mn-SOD, Cu/Zn-SOD and catalase, increases in glutathione peroxidase activity and activation of vascular nicotinamide adenine dinucleotide phosphate [(NAD(P)H] oxidase and p22phox expression; (iv) heat shock protein (HSP) expression by stimulating HSP70 expression in myocardium, skeletal muscle and even in human leucocytes, probably through heat shock transcription factor 1 activity; (v) inflammation by reducing serum inflammatory cytokines such as high-sensitivity C-reactive protein (hCRP), interleukin (IL)-6, IL-18 and tumour necrosis factor-alpha and by regulating Toll-like receptor 4 pathway. Exercise also alters vascular remodelling, which involves two forms of vessel growth including angiogenesis and arteriogenesis. Angiogenesis refers to the formation of new capillary networks. Arteriogenesis refers to the growth of pre-existent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. Another aim of this review is to focus on exercise-related cardiovascular protection against CVD and associated risk factors such as aging, coronary heart disease, hypertension, heart failure, diabetes mellitus and peripheral arterial diseases mediated by vascular remodelling. Lastly, this review examines the benefits of exercise in mitigating pre-eclampsia during pregnancy by mechanisms that include improved blood flow, reduced blood pressure, enhanced placental growth and vascularity, increased activity of antioxidant enzymes, reduced oxidative stress and restored vascular endothelial dysfunction.
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PMID:Exercise, vascular wall and cardiovascular diseases: an update (Part 1). 1902 18

While the stress response to heat and exercise is limited in the heart with progressive aging, recent data indicate that acute or short-term exercise upregulates the Mn isoform of superoxide dismutase (MnSOD), which may provide protection against ischemia-reperfusion injury and cell death by reducing oxidative stress. Growing evidence indicates that inducible nitric oxide synthase (iNOS) contributes to age-induced increases in oxidative stress and risk of heart failure. We postulated that oxidative stress and iNOS levels would be related to the ability of the aging heart to upregulate MnSOD in response to long-term exercise training. Six- and twenty-seven-mo-old Fischer-344 rats had been assigned to young sedentary (YS), young exercise (YE), old sedentary (OS), or old exercise (OE) groups. ET groups ran on a treadmill for 60 min/day, 5 days/wk for a total of 12 wk. MnSOD protein expression in the left ventricle was increased (+43%) by 12 wk of exercise training in the old age group, with no changes in Cu,ZnSOD. Exercise training also increased MnSOD activity in left ventricles from old and young rats. HSP70 was inducible by exercise training in hearts exclusively from the young age group. iNOS protein expression increased markedly with aging (+548%), while exercise training decreased iNOS levels by -73% in OE compared with OS. In addition, 4-hydroxynonenal protein adducts in the left ventricle increased by 237% with aging, while 12 wk of exercise training resulted in attenuation (-55%). These data indicate that inducibility of MnSOD is preserved with long-term exercise training in the aging rat heart. Moreover, upregulation of MnSOD in the aging heart was directly associated with attenuated levels of oxidative stress, including iNOS.
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PMID:Exercise training inducibility of MnSOD protein expression and activity is retained while reducing prooxidant signaling in the heart of senescent rats. 1929 46

Copper promotion of angiogenesis has been known for more than two decades, but the mechanism of action of copper has not been explored until recently. Copper stimulation of factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), is mainly responsible for its angiogenesis effect. Copper is required for the activation of hypoxia-inducible factor-1 (HIF-1), a major transcription factor regulating the expression of VEGF. Copper would be transported into nucleus by a copper chaperon for superoxide dismutase-1. Copper is required for HIF-1 interaction with the hypoxia-responsive element of the target genes and ensures the formation of HIF-1 transcriptional complex, thus activating the expression of target genes including VEGF. On the other hand, excess copper can stabilize HIF-1alpha, the rate-limiting component of HIF-1, leading to its accumulation in cytoplasm and thus HIF-1 activation. The essential role of copper in production of VEGF makes it implicated in anti-angiogenesis therapy, such as the application of copper chelators in cancer therapy. However, suppression of angiogenesis is involved in the progression of heart hypertrophy and its transition to heart failure, therefore copper supplementation improves hypertrophic heart disease conditions. This dilemma of copper implications in cancer therapy and heart hypertrophy dictates a comprehensive understanding of a patient's condition before an implementation of copper manipulation therapy for different diseases. In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy.
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PMID:Role of copper in angiogenesis and its medicinal implications. 1935 87

Statins and coenzyme Q10 are both used as adjuncts in the treatment of chronic heart failure (CHF) due to their anti-inflammatory and antioxidant effects, respectively. And both have been variously shown to improve cardiac function in patients with CHF. The two agents interact in two ways; statins inhibit coenzyme Q10 synthesis through inhibition of HMG-CoA reductase, the rate limiting step in cholesterol synthesis, also shared by coenzyme Q10. Secondly, they both exhibit their antioxidant effects through activation of the enzyme superoxide dismutase, the rate limiting step in nitric oxide metabolism and main antioxidant mechanism of coenzyme Q10. We hypothesize that the interaction between statins and coenzyme Q10 is more than just a replacement, but a synergistic interaction on superoxide dismutase that could result in better cardiac function, improvement in patient symptoms, shortening of duration of hospital stay and improvement in patient quality of life.
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PMID:Combined statin/coenzyme Q10 as adjunctive treatment of chronic heart failure. 1940 11

The sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are well recognized hallmarks of several cardiopathologic conditions, like cardiac ischemia/reperfusion (I/R) and heart failure (HF). The present work aimed to investigate the proteomics and energetic metabolism of cardiomyocytes incubated with ADR and/or ROS. To mimic pathologic conditions, freshly isolated calcium-tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (XXO)]. Two-dimensional electrophoresis with matrix-assisted laser desorption/ionization and time-of-flight mass spectrometer analysis were used to define protein spot alterations in the cardiomyocytes incubated with ADR and/or ROS. Moreover, the energetic metabolism and the activity of mitochondrial complexes were evaluated by nuclear magnetic resonance and spectrophotometric determinations, respectively. The protein extract was mainly constituted by cardiac mitochondrial proteins and the alterations found were included in five functional classes: (i) structural proteins, notably myosin light chain-2; (ii) redox regulation proteins, in particular superoxide dismutase (SOD); (iii) energetic metabolism proteins, encompassing ATP synthase alpha chain and dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex; (iv) stress response proteins, like the heat shock proteins; and (v) regulatory proteins, like cytochrome c and voltage-dependent anion channel 1. The XXO system elicited alterations in cardiac contractile proteins, as they showed high levels of cleavage, and also altered energetic metabolism, through increased lactate and alanine levels. The cardiomyocytes incubation with ADR resulted in an accentuated increase in mitochondrial complexes activity and the decrease in alanine/lactate ratio, thus reflecting a high cytosolic NADH/NAD(+) ratio. Furthermore, an increase in manganese SOD expression and total SOD activity occurred in the ADR group, as the increase in the mitochondrial complexes presumably led to higher 'electron leakage'. The modifications in proteins, enzymes activity, and energetic metabolism were indicative that different pathways are activated by catecholamines and ROS. These alterations altogether determine the I/R and HF specific features and contribute for the initiation or aggravation of those cardiopathologic conditions.
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PMID:Adrenaline and reactive oxygen species elicit proteome and energetic metabolism modifications in freshly isolated rat cardiomyocytes. 1946 73


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