Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
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PMID:Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. 1587 5

The octapeptide angiotensin II (ANG II) can modulate cardiac contractility and is increased in heart failure, where contractile function is impaired. In rat cardiac myocytes, 1 microM of ANG II produces a negative inotropic effect (NIE) (24.6 +/- 5% reduction). However, the subcellular signaling involved in this effect remains elusive. We examined the mechanisms and signaling events involved in the reduction in contractile function induced by the peptide in indo-1-loaded rat cardiomyocytes. The results showed that the NIE of ANG II was not associated with a parallel decrease in the intracellular Ca2+ transient, indicating that a decrease in myofilament responsiveness to Ca2+ underlies the reduction in contractility. We assessed the role of PKC, tyrosine kinases, reactive oxygen species (ROS), and mitogen-activated protein kinases (MAPKs) in the NIE of the peptide. Pretreatment of cells with the NAD(P)H oxidase inhibitor diphenyleneiodonium chloride or with the superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid did not affect the ANG II-induced NIE. Moreover, ANG II-induced ROS production, after 20 min of incubation with the peptide, could not be detected with the use of either the fluorophore 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorecein diacetate or lucigenin-enhanced chemiluminescence. In contrast, the ANG II-induced NIE was abrogated by the inhibitors of PKC (calphostin C), tyrosine kinase (genistein), and p38 MAPK (SB-202190). Furthermore, the NIE was significantly exacerbated (60 +/- 10% reduction) by p38 MAPK overexpression. These results exclude the participation of ROS in the NIE of the peptide and point to PKC and tyrosine kinase as upstream mediators. Furthermore, they reveal p38 MAPK as the putative effector of the reduction in myofilament responsiveness to Ca2+ and the decrease in contractility induced by the peptide.
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PMID:Angiotensin II-induced negative inotropy in rat ventricular myocytes: role of reactive oxygen species and p38 MAPK. 1637 94

Intracellular ROS (reactive oxygen species) such as superoxide and H2O2 have been increasingly appreciated to have a role in endothelial pathophysiology. Of the several sources within the vasculature, a family of multi-subunit NADPH oxidases appears to be a predominant contributor of endothelial superoxide. More importantly, this enzyme system is activated by numerous stimuli and is involved in triggering diverse intracellular signalling pathways ('redox-sensitive' signalling pathways) that have a central role in conditions such as endothelial activation and inflammation, cell growth, apoptosis and hypertrophy. Furthermore, NADPH oxidase-derived superoxide contributes to the impairment of endothelium-dependent vasodilatation by inactivating nitric oxide; the resultant endothelial dysfunction is implicated in the pathophysiology of diseases such as atherosclerosis, hypertension, diabetic vasculopathy and heart failure. A detailed understanding of the regulation of NADPH oxidases and their modulation and downstream effects may define novel therapeutic targets for cardiovascular disease prevention and treatment in the clinical setting, in contrast with global antioxidant therapy which has to date been disappointing.
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PMID:NADPH oxidase and endothelial cell function. 1610 42

Recent studies indicate the presence of vascular alterations in 2-month-old Syrian cardiomyopathic hamsters (SCH). These alterations include enhanced angiotensin-converting enzyme (ACE) activity in the aorta, increased contractile response to angiotensin II and impaired vasorelaxation to acetylcholine in norepinephrine-precontracted aortic rings. The mechanisms leading to these vascular alterations are not known nor has their relationship to the cardiac abnormalities been established. We assessed the status of the cardiovascular system of 2-month-old hamsters first to establish if the observed vascular alterations are secondary to cardiac dysfunction, and second to examine the role of oxidative stress in the etiology of vascular dysfunction. Cardiac function parameters evaluated by echocardiography included stroke volume (SV), left ventricular end-diastolic volume (LVEDV), left ventricular fractional shortening (LVFS), ejection fraction (EF), cardiac output index (COI), heart rate (HR) and left ventricular posterior wall thickness (LVPWT). In addition, heart/body weight (heart/BW) ratios and systolic blood pressure were determined in normal hamsters and SCH. Our results indicated that systolic blood pressure increased 56% in SCH when compared to control animals (P<0.05). The increased blood pressure coexisted with normal COI, SV, LVEDV, LVPWT, LVFS, EF, HR and heart/BW ratios. NAD(P)H oxidase activity increased 77% in SCH compared to control animals (P<0.02). The increased oxidase activity was abolished by pre-treatment of animals with the angiotensin II type 1 receptor blocker losartan (25 mg/kg BW/day) for 10 days. Losartan also abolished the increased blood pressure observed at 2 months of age. The antioxidant N-acetylcysteine (NAC) abrogated the increased blood pressure when administered for 30 days to 1-month-old animals. Altogether, these findings suggest that the angiotensin II-dependent vascular abnormalities present in young cardiomyopathic hamsters are associated with oxidative stress and precede the echocardiographic abnormalities characteristic of heart failure.
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PMID:Angiotensin II-dependent vascular alterations in young cardiomyopathic hamsters: role for oxidative stress. 1630 Oct 3

Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease.
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PMID:NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology. 1632 3

Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31+/-3% versus 67+/-3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7+/-0.2 mm versus 7.0+/-0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.
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PMID:Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. 1645 8

Angiotensin II stimulates NADPH oxidase activity in vascular cells. However, it is not fully understood whether angiotensin II, which plays an important role in heart failure, stimulates NADPH oxidase activation and expression in cardiac myocytes. Previous studies have shown that angiotensin II induces myocyte apoptosis, but whether the change is mediated via NADPH oxidase remains to be elucidated. In this study we proposed to determine whether angiotensin II stimulated NADPH oxidase activation and NADPH oxidase subunit p47-phox expression in H9C2 cardiac muscle cells. If so, we would determine whether the NADPH oxidase inhibitor apocynin prevented angiotensin II-induced apoptosis. The results showed that angiotensin II increased NADPH oxidase activity, p47-phox protein and mRNA expression, intracellular reactive oxygen species, and apoptosis in H9C2 cells. Angiotensin II elevated p38 mitogen-activated protein kinase (MAPK) activity, decreased Bcl-2 protein, and increased Bax protein and caspase-3 activity. Apocynin treatment inhibited angiotensin II-induced NADPH oxidase activation and increases in p47-phox expression, intracellular reactive oxygen species, and apoptosis. The effect of apocynin on apoptosis was associated with reduced p38 MAPK activity, increased Bcl-2 protein, and decreased Bax protein and caspase-3 activity. These results suggest that angiotensin II-induced apoptosis is mediated via NADPH oxidase activation probably through p38 MAPK activation, a decrease in Bcl-2 protein, and caspase activation.
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PMID:NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac muscle cells: effects of apocynin. 1641 6

Reactive oxygen species play important roles in the pathophysiology of chronic heart failure secondary to chronic left ventricular hypertrophy or myocardial infarction. Reactive oxygen species influence several components of the phenotype of the failing heart, including contractile function, interstitial fibrosis, endothelial dysfunction and myocyte hypertrophy. Recent studies implicate the production of reactive oxygen species by a family of NADPH oxidases in these effects. NADPH oxidases are activated in an isoform-specific manner by many pathophysiological stimuli and exert distinct downstream effects. Understanding NADPH oxidase activation and regulation, and their downstream effectors, could help to develop novel therapeutic targets.
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PMID:NADPH oxidase and heart failure. 1648 50

Chronic elevation of circulating ANG II is associated with cardiac remodeling in patients with hypertension and heart failure. The underlying mechanisms, however, are not completely defined. Herein, we studied ANG II-induced molecular and cellular events in the rat heart as well as their links to the redox state. We also addressed the potential contribution of aldosterone (ALDO) on ANG II-induced cardiac remodeling. In ANG II-treated rats, and compared with controls, we found: 1) the expression of proinflammatory/profibrogenic mediators was significantly increased in the perivascular space and at the sites of microscopic injury in both ventricles; 2) macrophages and myofibroblasts were primary repairing cells at these sites, together with increased fibrillar collagen volume; 3) apoptotic macrophages and myofibroblasts were evident at the same sites; 4) NADPH oxidase (gp91phox) was significantly enhanced at these regions and primarily expressed by macrophages, whereas superoxide dismutase and catalase levels remained unchanged; 5) plasma 8-isoprostane levels were significantly increased; and 6) blood pressure was significantly elevated. Losartan treatment completely prevented cardiac oxidative stress as well as molecular/cellular responses and normalized blood pressure. Spironolactone treatment partially suppressed the cardiac inflammatory/fibrogenic responses and redox state. Thus chronic elevation of circulating ANG II is accompanied by a proinflammatory/profibrogenic phenotype involving vascular and myocardial remodeling in both ventricles. Enhanced reactive oxygen species production at these sites and increased plasma 8-isoprostane indicate the involvement of oxidative stress in ANG II-induced cardiac injury. ALDO contributes, in part, to ANG II-induced cardiac molecular and cellular responses.
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PMID:ANG II-induced cardiac molecular and cellular events: role of aldosterone. 1648 2

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11beta-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.
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PMID:Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. 1650 9


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