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)

Tumor necrosis factor-alpha (TNF-alpha) has been shown to reduce endothelial nitric-oxide synthase (eNOS) gene expression through post-transcriptional regulation of mRNA stability. The current study documented an independent effect of the cytokine on the eNOS gene promoter. TNF-alpha effected a time- and dose-dependent reduction in activity of a transiently transfected human -1197 eNOS-luciferase reporter. This reduction was inhibited by co-transfection of dominant negative IKKbeta as well as a nonphosphorylatable constitutively suppressive mutant of IkappaB implying involvement of the NFkappaB cascade in the inhibitory effect. The locus of the TNF-alpha-dependent inhibition was traced to two Sp1-binding sites positioned between -109 and -95 and -81 and -67 relative to the transcription start site. Electrophoretic mobility shift analysis and immunoperturbation studies showed evidence for Sp1 and Sp3 binding to each element. TNF-alpha treatment had no effect on the binding pattern to the downstream (-81 to -67) site but did suppress association of Sp1 and Sp3 to the upstream (-109 to -95) site. Collectively, these data indicate that TNF-alpha exerts transcriptional, as well as post-transcriptional, effects on eNOS gene expression and suggest a potential mechanism to account for the endothelial dysfunction that accompanies disorders such as diabetes mellitus and heart failure.
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PMID:Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells. 1458 70

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), which has been characterized as an "endogenous anti-atherosclerotic molecule". Synthesis of NO can be selectively inhibited by guanidino-substituted analogs of L-arginine, which act as competitive inhibitors at the active site of the enzyme. One such analog is asymmetric dimethylarginine (ADMA), a compound that has been found in human plasma and urine and exerts the activity of an endogenous inhibitor of NO synthase. In contrast to ADMA, its regioisomer symmetric dimethylarginine (SDMA) does not inhibit NO synthase. The methyl groups contained within the dimethylarginine molecules are derived from S-adenosylmethionine, an intermediate in the homocysteine/methionine pathway. There is experimental evidence that homocysteine may affect endothelium-dependent vascular function by increasing the formation of ADMA. Both ADMA and SDMA are eliminated from the body by renal excretion. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations found in pathophysiological conditions (i.e., 3-15 microM). ADMA likely acts as an autocrine regulator of endothelial NO synthase activity. When rabbits are placed on a diet enriched with 1% cholesterol, ADMA levels are increased within 4 weeks of dietary intervention as compared to control animals. Elevated plasma concentrations of ADMA are also present in hypercholesterolemic and hypertensive patients, in patients with chronic heart failure, and in other patient groups at high risk of developing cardiovascular disease. Elevation of ADMA induces dysfunction of the endothelium, which becomes clinically evident by impaired endothelium-dependent vasodilation, hyperaggregability of platelets, and enhanced monocyte adhesion. Recent prospective studies suggest that endothelial dysfunction indicates an increased risk of future cardiovascular events. In line with these observations, we and others found evidence that ADMA is a novel cardiovascular risk factor.
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PMID:Association of asymmetric dimethylarginine and endothelial dysfunction. 1465 27

There is abundant evidence now that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intra-arterially. ADMA is increased in plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk in certain populations like hemodialysis patients, non-smoking men, or intensive-care patients. The CARDIAC study is a multicenter case-control study designed to address the hypothesis that ADMA may be a suitable and sensitive marker of cardiovascular risk in a large, unselected population of both sexes, and with a broad range of established cardiovascular risk factors. The population included in the CARDIAC study will be prospectively followed for a scheduled follow-up period of 4 years, and the data of the CARDIAC-PRO study will then provide definite evidence whether ADMA may be prospectively determined as a cardiovascular risk factor.
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PMID:Plasma concentration of asymmetric dimethylarginine and the risk of coronary heart disease: rationale and design of the multicenter CARDIAC study. 1466

It has been shown that peripheral chemoreceptor sensitivity is enhanced in both clinical and experimental heart failure (HF) and that impairment of nitric oxide (NO) production contributes to this enhancement. In order to understand the cellular mechanisms associated with the alterations of chemoreceptor function and the actions of NO in the carotid body (CB), we compared the outward K+ currents (IK) of glomus cells in sham rabbits with that in HF rabbits and monitored the effects of NO on these currents. Ik was measured in glomus cells using conventional and perforated whole-cell configurations. IK was attenuated in glomus cells of HF rabbits, and their resting membrane potentials (-34.7 +/- 1.0 mV) were depolarized as compared with those in sham rabbits (-47.2 +/- 1.9 mV). The selective Ca(2+)-dependent K+ channel (KCa) blocker iberiotoxin (IbTx, 100 nm) reduced IK in glomus cells from sham rabbits, but had no effect on IK from HF rabbits. In perforated whole-cell mode, the NO donor SNAP (100 microm) increased IK in glomus cells from HF rabbits to a greater extent than that in sham rabbits (P < 0.01), and IbTx inhibited the effects of SNAP. However, in conventional whole-cell mode, SNAP had no effect. N omega-nitro-L-arginine (L-NNA, NO synthase inhibitor) decreased Ik in sham rabbits but not in HF rabbits. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) inhibited the effect of SNAP on Ik. These results demonstrate that IK is reduced in CB glomus cells from HF rabbits. This effect is due mainly to the suppression of KCa channel activity caused by decreased availability of NO. In addition, intracellular cGMP is necessary for the KCa channel modulation by NO.
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PMID:Attenuated outward potassium currents in carotid body glomus cells of heart failure rabbit: involvement of nitric oxide. 1467 83

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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PMID:Apoptosis and heart failure: mechanisms and therapeutic implications. 1472 98

The purpose of this study was to determine the effect of nitric oxide (NO) in the rostral ventrolateral medulla (RVLM) on the central integration of the cardiac sympathetic afferent reflex (CSAR) in normal rats and in rats with coronary ligation-induced chronic heart failure (CHF). Under alpha-chloralose and urethane anesthesia, mean arterial pressure, heart rate and renal sympathetic nerve activity (RSNA) were recorded at baseline and during elicitation of the CSAR evoked by electrical stimulation of the cardiac afferent sympathetic nerves in sino-aortic denervated and cervical vagotomized rats. A cannula was inserted into the left RVLM for microinjection of NO synthase inhibitor, S-methyl-L-thiocitruline (MeTC) or NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). The CSAR was tested by electrical stimulation (5, 10, 20 and 30 Hz at 10 V for 1 ms) of the afferent cardiac sympathetic nerves. It was observed that (1) the responses of RSNA to stimulation were enhanced in rats with CHF; (2) MeTC (80 nmol) potentiated the responses of RSNA to stimulation in sham rats but not in rats with CHF; (3) SNAP (50 nmol) depressed the enhanced RSNA response to stimulation in CHF rats but had no effect in sham rats; and (4) MeTC increased the baseline RSNA and MAP only in sham rats, but SNAP inhibited the baseline RSNA and MAP in both sham and CHF rats. These results indicate that reductance of NO in the RVLM is involved in the augmentation of CSAR in CHF rats.
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PMID:Reduced nitric oxide in the rostral ventrolateral medulla enhances cardiac sympathetic afferent reflex in rats with chronic heart failure. 1498 29

Several cell types, including cardiac myocytes and vascular endothelial cells, produce nitric oxide (NO) via both constitutive and inducible isoforms of NO synthase. NO attenuates cardiac contractility and contributes to contractile dysfunction in heart failure, although the precise molecular mechanisms for these effects are poorly defined. Adenylyl cyclase (AC) isoforms type 5 and 6, which are preferentially expressed in cardiac myocytes, may be inhibited via a direct nitrosylation by NO. Because endothelial NO synthase (eNOS and NOS3), beta-adrenergic (betaAR) receptors, and AC6 all can localize in lipid raft/caveolin-rich microdomains, we sought to understand the role of lipid rafts in organizing components of betaAR-G(s)-AC signal transduction together with eNOS. Using neonatal rat cardiac myocytes, we found that disruption of lipid rafts with beta-cyclodextrin inhibited forskolin-stimulated AC activity and cAMP production, eliminated caveolin-3-eNOS interaction, and increased NO production. betaAR- and G(s)-mediated activation of AC activity were inhibited by beta-cyclodextrin treatment, but prostanoid receptor-stimulated AC activity, which appears to occur outside caveolin-rich microdomains, was unaffected unless eNOS was overexpressed and lipid rafts were disrupted. An NO donor, SNAP, inhibited basal and forskolin-stimulated cAMP production in both native cardiac myocytes and cardiac myocytes and pulmonary artery endothelial cells engineered to overexpress AC6. These effects of SNAP were independent of guanylyl cyclase activity and were mimicked by overexpression of eNOS. The juxtaposition of eNOS with betaAR and AC types 5 and 6 results in selective regulation of betaAR by eNOS activity in lipid raft domains over other G(s)-coupled receptors localized in nonraft domains. Thus co-localization of multiple signaling components in lipid rafts provides key spatial regulation of AC activity.
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PMID:Nitric oxide inhibition of adenylyl cyclase type 6 activity is dependent upon lipid rafts and caveolin signaling complexes. 1500 69

There is growing evidence that endothelial dysfunction, which is often defined as the decreased endothelial-derived nitric oxide (NO) bioavailability, is a crucial factor leading to vascular disease states such as hypertension, diabetes, atherosclerosis, heart failure and cigarette smoking. This is due to the fact that the lack of NO in endothelium-dependent vascular disorders contributes to impaired vascular relaxation, platelet aggregation, increased vascular smooth muscle proliferation, and enhanced leukocyte adhesion to the endothelium. During the last several years, it has become clear that reduction of NO bioavailability in the endothelium-impaired function disorders is associated with an increase in endothelial production of superoxide (O(2)(*-)). Because O(2)(*-) rapidly scavenges NO within the endothelium, a reduction of bioactive NO might occur despite an increased NO generation. Among many enzymatic systems that are capable of producing O(2)(*-), NAD(P)H oxidase and uncoupled endothelial NO synthase (eNOS) apparently are the main sources of O(2)(*-) in the endothelial cells. It seems that O(2)(*-) generated by NAD(P)H oxidase may trigger eNOS uncoupling and contribute to the endothelial balance between NO and O(2)(*-). That is maintained at diverse levels.
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PMID:Endothelial NADH/NADPH-dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction. 1521 42

Although initially adaptive, the changes that accompany hypertension, namely, cell growth, endothelial dysfunction, and extracellular matrix deposition, eventually can become maladaptive and lead to end-organ disease such as heart failure, coronary artery disease, and renal failure. A functional imbalance between angiotensin II (Ang II) and nitric oxide (NO) plays an important pathogenetic role in hypertensive end-organ injury. NO, an endogenous vasodilator, inhibitor of vascular smooth muscle and mesangial cell growth, and natriuretic agent, is synthesized in the endothelium by a constitutive NO synthase. NO antagonizes the effects of Ang II on vascular tone, cell growth, and renal sodium excretion, and also down-regulates the synthesis of angiotensin-converting enzyme (ACE) and Ang II type 1 receptors. On the other hand, Ang II decreases NO bioavailability by promoting oxidative stress. A better understanding of the pathophysiologic mechanisms involved in hypertensive end-organ damage may aid in identifying markers of cardiovascular susceptibility to injury and in developing therapeutic interventions. We propose that those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as Ang II and NO within the vessel wall would be more effective in preventing or arresting end-organ disease.
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PMID:Nitric oxide, angiotensin II, and hypertension. 1525 76

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6-8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18-20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 +/- 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 +/- 5.4% of baseline, which was significantly attenuated compared with sham rats (P < 0.01). In sham rats, the pressor response was completely abolished by alpha-receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of HR responses. The tachycardia could not be abolished by the beta(1)-blocker metoprolol. However, the muscarinic receptor antagonist atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.
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PMID:Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure. 1533 68


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