Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asymmetrical dimethyl-L-arginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. We hypothesized that plasma levels of ADMA could be increased in patients with congenital heart disease and pulmonary hypertension. Cardiac catheterization was performed in 20 children and young adults with congenital heart disease with a median age of 10 years (range, 4 months to 33 years). The patients were assigned to group I (high flow, low pressure; n = 14) when Qp/Qs was 1.5 or greater and the mean PAP was less than 25 mm Hg or to group II (high pressure, high resistance; n = 6) when the mean PAP was greater than 25 mm Hg and Rp/Rs was greater than 0.3. Blood samples were taken from pulmonary vein or left ventricle. ADMA was measured by high-performance liquid chromatography. In addition, levels of ADMA were measured in peripheral venous blood obtained from eight control patients. Levels of ADMA in control patients (median, 0.21 microM/l; range, 0.08-0.27 microM/l) did not differ from levels obtained in group I (median, 0.30 microM/l; range, 0.06-0.49) microM/l). Patients in group II showed increased plasma levels of ADMA (median, 0.55; range, 0.25-0.79) (p < 0.01). Inhibition of nitric oxide synthase by increased levels of ADMA might contribute to pulmonary hypertension in patients with congenital heart disease.
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PMID:Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. 1130 Jun 62

Brugada syndrome is an inherited cardiac disorder caused by mutations in the cardiac sodium channel gene, SCN5A, that leads to ventricular fibrillation and sudden death. This study reports the changes in functional expression and cellular localization of an SCN5A double mutant (R1232W/T1620M) recently discovered in patients with Brugada syndrome. Mutant and wild-type (WT) human heart sodium channels (hNa(v)1.5) were expressed in tsA201 cells in the presence of the beta(1)-auxiliary subunit. Patch-clamp experiments in whole-cell configuration were conducted to assess functional expression. Immunohistochemistry and confocal microscopy were used to determine the spatial distribution of either WT or mutant cardiac sodium channels. The results show an abolition of functional sodium channel expression of the hNa(v)1.5/R1232W/T1620M mutant in the tsA201 cells. A conservative positively charged mutant, hNa(v)1.5/R1232K/T1620M, produced functional channels. Immunofluorescent staining showed that the FLAG-tagged hNa(v)1.5/WT transfected into tsA201 cells was localized on the cell surface, whereas the FLAG-tagged hNa(v)1.5/R1232W/T1620M mutant was colocalized with calnexin within the endoplasmic reticulum (ER). These results indicate that a positively charged arginine or lysine residue at position 1232 in the double mutant is required for the proper transport and functional expression of the hNa(v)1.5 protein. These results support the concept that loss of function of the cardiac Na(+) channel is responsible for the Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
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PMID:Expression and intracellular localization of an SCN5A double mutant R1232W/T1620M implicated in Brugada syndrome. 1178 29

Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nomega-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NO(X) levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.
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PMID:Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. 1214 1

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B2 kinin receptor (B2R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h) edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.
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PMID:Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor (B1/B2) subtypes. 1242 28

Arginine-vasopressin (AVP) may be more effective than epinephrine in shock states and as an end-of-life salvage maneuver. However, there is only limited experience using AVP in children. Our study aim was to evaluate the effect of AVP administration on hemodynamic and ventilatory parameters in critically ill children. Eight critically ill children (1 month to 12 years old) were treated with AVP during the years 2000-2001. Two patients had had head trauma, and six had surgical correction of congenital heart disease. All patients suffered severe septic or cardiogenic shock with a low cardiac output state and were considered to be near death. AVP was administered continuously at a dose of 0.0003-0.002 U/kg/min. Hemodynamic and ventilatory parameters and vasopressor doses were compared before and after AVP initiation. One patient survived with a good neurologic outcome. Seven patients succumbed while receiving AVP. Systolic and diastolic blood pressure increased significantly (P < 0.03) following AVP initiation. The epinephrine requirement decreased from 2.3 to 1.7 microg/kg/min. Blood gases improved with a significant (P < 0.05) increase of PaO2. Oxygenation index and PaO2/FiO2 ratio improved significantly, and ventilatory support requirements and positive inspiratory pressure (PIP) decreased significantly. Despite a significant improvement in hemodynamic and ventilatory support parameters, survival to hospital discharge was not achieved when AVP was used in critically ill pediatric patients. We hypothesize that earlier administration of AVP may be more beneficial.
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PMID:Intravenous arginine vasopressin in critically ill children: is it beneficial? 1531 89

We have used molecular dynamics simulations to investigate the effect of phosphorylation and mutation on the cytoplasmic domain of phospholamban (PLB), a 52-residue protein that regulates the calcium pump in cardiac muscle. Simulations were carried out in explicit water systems at 300 K for three peptides spanning the first 25 residues of PLB: wild-type (PLB(1-25)), PLB(1-25) phosphorylated at Ser16 and PLB(1-25) with the R9C mutation, which is known to cause human heart disease. The unphosphorylated peptide maintains a helical conformation from 3 to 15 throughout a 26-ns simulation, in agreement with spectroscopic data. Comparison with simulations of a fourth peptide truncated at Pro21 showed the importance of the region from 17 to 21 in preventing local unfolding of the helix. The results suggest that residues 11-16 are more likely to unfold when specific capping motifs are not present. It is proposed that protein kinase A exploits the intrinsic flexibility of the 11-21 region when binding PLB. In agreement with available CD and NMR data, the simulations show a decrease in the helical content upon phosphorylation. The phosphorylated peptide is characterized by helix spanning residues 3-11, followed by a turn that optimizes the salt-bridge interaction between the side chains of the phosphorylated Ser-16 and Arg-13. Replacing Arg-9 with Cys results in unfolding of the helix from C9 and an overall decrease of the helical conformation. The simulations show that initiation of unfolding is due to increased solvent accessibility of the backbone atoms near the smaller Cys. It is proposed that the loss of inhibitory potency upon Ser-16 phosphorylation or R9C mutation of PLB is due to a similar mechanism, in which the partial unfolding of the cytoplasmic helix of PLB results in a conformation that interacts with the cytoplasmic domain of the calcium pump to relieve its inhibition.
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PMID:The alpha-helical propensity of the cytoplasmic domain of phospholamban: a molecular dynamics simulation of the effect of phosphorylation and mutation. 1576 55

Coxsackievirus B3 (CVB3) is a common human pathogen that is endemic throughout the world. There is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. Previously, we showed that the virulence of CVB3 is reduced by a lysine-to-arginine substitution in the capsid protein VP2 (K2168R) or a glutamic acid-to-glycine substitution in VP3 (E3060G). In this report, we show that the double mutant virus CVB3(KR/EG) displays additional attenuation, particularly for the pancreas, in A/J mice. In addition, two other attenuating mutations have been identified in the capsid protein VP1. When either the aspartic acid residue D1155 was replaced with glutamic acid or the proline residue P1126 was replaced with methionine, the resulting mutant also possessed an attenuated phenotype. Moreover, when either of these mutations was incorporated into CVB3(KR/EG), the resulting triple mutant viruses, CVB3(KR/EG/DE) and CVB3(KR/EG/PM), were completely noncardiovirulent and caused only small foci of damage to the pancreas, even at a high dose. Both triple mutants were found to be immunogenic, and a single injection of young A/J mice with either was found to protect them from a subsequent lethal challenge with wild-type CVB3. These findings indicate that the triple mutants could be exploited for the development of a live attenuated vaccine against CVB3.
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PMID:A genetically engineered attenuated coxsackievirus B3 strain protects mice against lethal infection. 1599 22

Apolipoprotein (apo) E4 is a risk factor for heart disease, Alzheimer's disease, and other forms of neurodegeneration, but the underlying mechanisms are unknown. Domain interaction, a structural property that distinguishes apoE4 from apoE2 and apoE3, results in more rapid turnover and lower plasma levels of apoE4. To determine whether domain interaction affects brain apoE levels, we analyzed brain homogenates from human apoE3 and apoE4 knock-in mice, wild-type mice, and Arg-61 apoE mice, in which domain interaction was introduced by gene targeting. As determined on Western blots, the hemibrain, cortex, hippocampus, and cerebellum of knock-in mice had 30-40% lower levels of apoE4 than apoE3, and Arg-61 mice had 25-50% lower apoE levels than wild-type mice. In the CSF, Arg-61 apoE level was 40% lower than the wild-type level. Arg-61 apoE mRNA levels were similar to or slightly higher than wild-type apoE mRNA levels. Thus, the lower Arg-61 apoE levels were not attributable to decreased mRNA levels. In culture medium from heterozygous Arg-61/wild-type and apoE4/apoE3 primary astrocytes, Arg-61 apoE and apoE4 levels were lower than wild-type apoE and apoE3, respectively, suggesting that primary astrocytes secrete lower amounts of Arg-61 apoE and apoE4. These results demonstrate that domain interaction is responsible for the lower levels of both human apoE4 and mouse Arg-61 apoE in mouse brain. Cells may recognize apoE4 and Arg-61 apoE as misfolded proteins and target them for degradation or accumulation. Thus, degradation/accumulation or lower levels of apoE4 may contribute to the association of apoE4 with Alzheimer's disease.
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PMID:Effect of domain interaction on apolipoprotein E levels in mouse brain. 1629 38

It has been suggested that L-DOPA-induced hyperhomocysteinemia can increase the risk of stroke, heart disease, and dementia and is an additional pathogenetic factor involved in the progression of Parkinson's disease. In Chinese hamster ovary (CHO) cells stably cotransfected with adenosine A(2A) and dopamine D2 receptors, homocysteine selectively decreased the ability of D2 receptor stimulation to internalize adenosine A(2A)-dopamine D2 receptor complexes. Radioligand-binding experiments in the same cell line demonstrated that homocysteine acts as an allosteric D2 receptor antagonist, by selectively reducing the affinity of D2 receptors for agonists but not for antagonists. Mass spectrometric analysis showed that, by means of an arginine (Arg)-thiol electrostatic interaction, homocysteine forms noncovalent complexes with the two Arg-rich epitopes of the third intracellular loop of the D2 receptor, one of them involved in A(2A)-D2 receptor heteromerization. However, homocysteine was unable to prevent or disrupt A(2A)-D2 receptor heteromerization, as demonstrated with Fluorescence Resonance Energy Transfer (FRET) experiments in stably cotransfected HEK cells. The present results could have implications for Parkinson's disease.
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PMID:Allosteric modulation of dopamine D2 receptors by homocysteine. 1708 Oct 59

Endothelial dysfunction associated with elevated serum levels of TNF-alpha observed in diabetes, obesity, and congenital heart disease results, in part, from the impaired production of endothelial nitric oxide (NO). Cellular NO production depends absolutely on the availability of arginine, substrate of endothelial nitric oxide synthase (eNOS). In this report, evidence is provided demonstrating that treatment with TNF-alpha (10 ng/ml) suppresses not only eNOS expression but also the availability of arginine via the coordinate suppression of argininosuccinate synthase (AS) expression in aortic endothelial cells. Western blot and real-time RT-PCR demonstrated a significant and dose-dependent reduction of AS protein and mRNA when treated with TNF-alpha with a corresponding decrease in NO production. Reporter gene analysis demonstrated that TNF-alpha suppresses the AS proximal promoter, and EMSA analysis showed reduced binding to three essential Sp1 elements. Inhibitor studies suggested that the repression of AS expression by TNF-alpha may be mediated, in part, via the NF-kappaB signaling pathway. These findings demonstrate that TNF-alpha coordinately downregulates eNOS and AS expression, resulting in a severely impaired citrulline-NO cycle. The downregulation of AS by TNF-alpha is an added insult to endothelial function because of its important role in NO production and in endothelial viability.
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PMID:Tumor necrosis factor-alpha reduces argininosuccinate synthase expression and nitric oxide production in aortic endothelial cells. 1749 12


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