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)

Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO(x)) in middle-aged men. We also determined whether plasma NO(x) or NOS 3 genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4 NOS 3 gene polymorphisms: -786 T/C, -922 A/G, 894 G/T (which predicts a Glu(298)-->Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NO(x) was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the NOS 3 polymorphismsstudied, with the strongest allelic association being detected between -922 A/G and -786 T/C polymorphisms in the gene promoter (Delta=0.90, P<0.001). Plasma NO(x) was lower in smokers than in nonsmokers in the North Mymms (10.8+/-4.5 versus 11.8+/-4.6 micromol/L, P=0.13), Chesterfield (8.4+/-3.6 versus 9.9+/-4.0 micromol/L, P=0.01), and random samples (10.7+/-5.1 versus 11.7+/-4.7 micromol/L, P=0.03). A weak but significant inverse relationship was detected between plasma NO(x) and serum cholesterol only in the North Mymms data set (r=-0.14, P=0.02). No relationship was detected between plasma NO(x) and any of the NOS 3 polymorphisms, nor was there any association between any NOS 3 polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that NOS 3 genotype does not influence significantly the level of plasma NO(x) or the risk of IHD in this population sample of middle-aged British men.
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PMID:Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease. 1171 97

Previous studies have shown that estrogen modulation of endothelial nitric oxide (NO) synthase (eNOS) may confer protection against heart disease. Here, we demonstrate an association between reductions in baroreflex-mediated bradycardia and in cardiac NOS activity in ovariectomized (Ovx) rats compared with controls. The latter resulted, at least in part, from a reduction in cardiac eNOS protein. eNOS-derived NO and its biological effects are determined by the levels of eNOS protein and by eNOS catalytic activity; the latter is regulated partly through the dynamic interaction with an inhibitory protein (caveolin) and a stimulatory protein (calmodulin). The association of eNOS immunoprecipitated with caveolin-3 and calmodulin was examined. Caveolin-3 and calmodulin binding with eNOS was increased and decreased, respectively, in Ovx rats. 17 beta-Estradiol replacement restored, to within normal levels, the baroreflex-mediated bradycardic responses along with eNOS activity, eNOS expression, and the association of eNOS with caveolin-3 and calmodulin. Our findings may help to elucidate the molecular mechanism underlying the favorable effects of estrogen on cardiac responses to baroreflex activation.
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PMID:Estrogen modulation of eNOS activity and its association with caveolin-3 and calmodulin in rat hearts. 1200 41

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.
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PMID:Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure. 1515 68

Constitutive nitric oxide (NO) is generated by constitutively expressed types of NO-synthase enzymes (NOS-I and -III), being involved in physiological processes such as nervous transmission and vasodilatation. Inducible NO, synthesized by the NO-synthase isoform NOS-II, is an anti-pathogen and tumoricidal agent. However, inducible NO production requires a tight control because of cytotoxic and immune-modulation activity. NO produced by human and canine macrophages has long been demonstrated to be involved in the intracellular killing of Leishmania. Mechanisms of parasite survival and persistence in the host have been throughly investigated, and include suppression of NOS-II and the parasite entry into NOS-II negative cells. Both intracellular and extracellular morphotypes of Trypanosoma cruzi are killed by NO in vitro and in vivo, although a role of NO in the pathogenesis of heart disease has been reported. Killing of extracellular protozoa such as Trichomonas vaginalis and Naegleria fowleri by activated macrophages is also mediated by NO. The main control of Plasmodium spp infection in human and murine hepatocytes, and in human monocytes is achieved by NO-mediated mechanisms. Protection from severe malaria in African children has been found associated with polymorphisms of the NOS-II promoter; however, a pathogenic role of endogenous NO has been documented in cerebral malaria. Although several macromolecules are putative NO targets, recent experimental work has shown that NO-releasing compounds inhibit cysteine proteases (CP) of P. falciparum, T. cruzi and L. infantum in a dose-dependent manner. CPs are present in a wide range of parasitic protozoa and appear to be relevant in several aspects of the life cycle and of the parasite-host relationships. Comparative analysis of 3-D amino acid sequence models of CPs from a broad range of living organisms, from viruses to mammals, suggests that the Sy atom of the Cys catalytic residue undergoes NO-dependent chemical modification (S-nytrosilation and disulfide bridge formation), with the concomitant loss of enzyme activity. The NO-donor S-nitroso-N-acetilpenicillamine (SNAP) was shown to kill T. cruzi epimastigotes and L. infantum promastigotes in culture, while a combination of nitrite plus acid organic salts was highly effective against L. major amastigotes in mouse macrophages. A parasitostatic effect--with both encystation and excystation inhibition--of S-nitrosoglutathione and spermine-NONOate was documented in trophozoite cultures of Giardia duodenalis. Recently, a novel formulation of metronidazole bearing a NO-releasing group was found to enhance significantly the in vitro killing of Entamoeba histolytica trophozoites, compared to metronidazole. So far, only two clinical studies were performed on human patients, suffering from cutaneous leishmaniasis. In one study, 16 Ecuadorean patients were treated with a SNAP cream administered on lesions for 10 days. All lesions were parasitologically cured and clinically healed by day 30. In the second study, a different NO-producing cream (basically nitrite in acidic environment) was employed to treat 40 Syrian patients. Only 28% of them showed improvement and 12% were cured by day 60. In conclusion, despite the wide evidence that NO can be regarded as a natural anti-protozoal weapon, little efforts have been made to develop and test NO-based drugs in human medicine. This is mainly due to the difficulty in designing suitable chemical carriers able to release the right amount of NO, in the right place and in the right time, to avoid toxic effects against non-target host cells.
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PMID:[Nitric oxide and anti-protozoan chemotherapy]. 1530 96

Septicemia is an emerging pathological condition involving, among other effects, refractory hypotension and heart dysfunction. Here we have investigated the contribution of resident nonmyocytic cells to heart alterations after lipopolysaccharide administration. These cells contributed to the rapid infiltration of additional inflammatory cells that enhance the onset of heart disease through the release of inflammatory mediators. Early activation of resident monocytic cells played a relevant role on the infiltration process, mainly of major histocompatibility complex class II- and CD11b-positive cells. This infiltration was significantly impaired in animals lacking the nitric-oxide synthase-2 (NOS-2) gene or after pharmacological in-hibition of NOS-2 or cylooxygenase-2, suggesting a significant contribution of nitric oxide and prostanoids to the infiltration process. Under these conditions, the expression of NOS-2 and cylooxygenase-2 in the whole organ was attenuated because cardiomyocytes failed to express these enzymes. However, cardiomyocytes expressed and activated matrix metalloproteinase-9 through mechanisms regulated, at least in part, by nitric oxide and prostaglandins in an additive way. These results directly link the inflammatory response in the heart and extracellular matrix remodeling by the matrix metalloproteinases released by the cardiomyocytes, suggesting that activation and recruitment of inflammatory cells to the heart is a major early event in cardiac dysfunction promoted by septicemia.
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PMID:Infiltration of inflammatory cells plays an important role in matrix metalloproteinase expression and activation in the heart during sepsis. 1707 81

Protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. Although all PRMTs produce monomethyl arginine (MMA), type 1 PRMTs go on to form asymmetrically dimethylated arginine (ADMA), while type 2 enzymes form symmetrically dimethylated arginine (SDMA). PRMT1 is the major type 1 PRMT in vivo, thus it is the primary producer of the competitive NOS inhibitor, ADMA. Hence, potent inhibitors, which are highly selective for this particular isozyme, could serve as excellent therapeutics for heart disease. However, the design of such inhibitors is impeded by a lack of information regarding this enzyme's kinetic and catalytic mechanisms. Herein we report an analysis of the kinetic mechanism of human PRMT1 using both an unmethylated and a monomethylated substrate peptide based on the N-terminus of histone H4. The results of initial velocity and product and dead-end inhibition experiments indicate that PRMT1 utilizes a rapid equilibrium random mechanism with the formation of dead-end EAP and EBQ complexes. This mechanism is gratifyingly consistent with previous results demonstrating that PRMT1 catalyzes substrate dimethylation in a partially processive manner.
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PMID:Kinetic mechanism of protein arginine methyltransferase 1. 1877 Dec 93

Interactions of MinK and e-NOS Gene Polymorphisms Appear to Be Inconsistent Predictors of Atrial Fibrillation Propensity, but Long Alleles of ESR1 Promoter TA Repeat May Be a Promising Marker. We analyzed minK, e-NOS and ESR1 gene polymorphisms in 40 patients with atrial fibrillation (AF) without major structural heart disease compared to 35 healthy controls. A missense polymorphism in the minK gene with A/G substitution at nucleotide 112 causing serine (S) to glycine (G) change, 786 T/C polymorphism in the 5' flanking region of e-NOS gene and TA polymorphism in the regulatory region of estrogen receptor ESR1 gene with long (> or = 19 TA repeats) and short alleles were examined. Only a slight increase in minK G allele frequency, but with marked excess in AG/TT combination of minK and e-NOS polymorphisms was found in the AF group. The interpretation remains tentative due to small groups precluding statistical significance of differences, possible lab flaws and inconsistencies with earlier data. However, ESR1 long allele homozygotes were strikingly more frequent in the AF than in control group, reaching statistical significance surprisingly in males (p < 0.02). Functional activity of estrogen receptors may be more critical in males than in females with abundance of circulating estrogen. Contrasting the intricate complexity of genetic polymorphisms influencing cardiac rhythm with our modest research, we would limit the conclusion to the plea for further research of ESR1 role in AF.
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PMID:Interactions of MinK and e-NOS gene polymorphisms appear to be inconsistent predictors of atrial fibrillation propensity, but long alleles of ESR1 promoter TA repeat may be a promising marker. 1986 Jan 28

In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.
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PMID:An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. 2097 40

The development of pulmonary hypertension is a common accompaniment of congenital heart disease (CHD) with increased pulmonary blood flow. Our recent evidence suggests that asymmetric dimethylarginine (ADMA)-induced mitochondrial dysfunction causes endothelial nitric oxide synthase (eNOS) uncoupling secondary to a proteasome-dependent degradation of GTP cyclohydrolase I (GCH1) that results in a decrease in the NOS cofactor tetrahydrobiopterin (BH(4)). Decreases in NO signaling are thought to be an early hallmark of endothelial dysfunction. As l-carnitine plays an important role in maintaining mitochondrial function, in this study we examined the protective mechanisms and the therapeutic potential of l-carnitine on NO signaling in pulmonary arterial endothelial cells and in a lamb model of CHD and increased pulmonary blood flow (Shunt). Acetyl-l-carnitine attenuated the ADMA-mediated proteasomal degradation of GCH1. This preservation was associated with a decrease in the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) and a decrease in its ubiquitination. This in turn prevented the decrease in BH(4) levels induced by ADMA and preserved NO signaling. Treatment of Shunt lambs with l-carnitine also reduced GCH1/CHIP interactions, attenuated the ubiquitination and degradation of GCH1, and increased BH(4) levels compared to vehicle-treated Shunt lambs. The increases in BH(4) were associated with decreased NOS uncoupling and enhanced NO generation. Thus, we conclude that L-carnitine may have a therapeutic potential in the treatment of pulmonary hypertension in children with CHD with increased pulmonary blood flow.
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PMID:Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I. 2258 3

Nitric oxide is a key signaling molecule in the heart and is produced endogenously by three isoforms of nitric oxide synthase, neuronal NOS (NOS1), endothelial NOS (NOS3), and inducible NOS (NOS2). Nitric oxide signals via cGMP-dependent or independent pathways to modulate downstream proteins via specific post translational modifications (i.e. cGMP-dependent protein kinase phosphorylation, S-nitrosylation, etc.). Dysfunction of NOS (i.e. altered expression, location, coupling, activity, etc.) exists in various cardiac disease conditions, such as heart failure, contributing to the contractile dysfunction, adverse remodeling, and hypertrophy. This review will focus on the signaling pathways of each NOS isoform during health and disease, and discuss current and potential therapeutic approaches targeting nitric oxide signaling to treat heart disease.
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PMID:Targeting NOS as a therapeutic approach for heart failure. 2476 30


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