UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in alpha-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.
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PMID:Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. 1578 Dec 1

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the conversion of methylamine to formaldehyde. This enzyme is located on the surface of the cytoplasmic membrane and in the cytosol of vascular endothelial cells, smooth muscle cells, and adipocytes. Increased SSAO activity has been found in patients with diabetes mellitus, chronic heart failure, and multiple types of cerebral infarcts and is associated with obesity. Increased SSAO-mediated deamination may contribute to protein deposition, the formation of plaques, and inflammation, and thus may be involved in the pathophysiology of chronic vascular and neurological disorders, such as diabetic complications, atherosclerosis, and Alzheimer's disease. In the present study, we demonstrate the induction of cross-linkage of formaldehyde with the lysine moiety of peptides and proteins. Formaldehyde-protein adducts were reduced with sodium cyanoborohydride, hydrolyzed in hydrochloric acid, and the amino acids in the hydrolysates were derivatized with fluorenylmethyl chloroformate and then identified with high-performance liquid chromatography. We further demonstrate that incubation of methylamine in the presence of SSAO-rich tissues, e.g., human brain meninges, results in formaldehyde-protein cross-linkage of particulate bound proteins as well as of soluble proteins. This cross-linkage can be completely blocked by a selective inhibitor of SSAO. Our data support the hypothesis that the SSAO-induced production of formaldehyde may be involved in the alteration of protein structure, which may subsequently cause protein deposition associated with chronic pathological disorders.
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PMID:Protein cross-linkage induced by formaldehyde derived from semicarbazide-sensitive amine oxidase-mediated deamination of methylamine. 1512 65

Heart failure is a condition closely linked to diabetes. Hyperglycaemia amplifies the generation of a major advanced glycation end product Nepsilon-(carboxymethyl)lysine (CML), which has been associated with the development of vascular and inflammatory complications. An increased accumulation of CML in hearts of diabetic patients may be one of the mechanisms related to the high risk of heart failure. Therefore, we investigated the localization of CML in diabetic hearts. To investigate the presence and accumulation of CML in tissues, a monoclonal anti-CML antibody was generated and characterised. With this novel monoclonal antibody against CML, the localization of CML was investigated by immunohistochemistry, in heart tissue of controls (n = 9) and heart tissue of diabetic patients (n = 8) without signs of inflammation or infarction. In addition, in the same subjects we studied the presence of CML in renal and lung tissues. CML staining was approximately sixfold higher in hearts from diabetic patients as compared to control hearts (2.0 +/- 0.3 and 0.3 +/- 0.2 A.U., respectively, P < 0.01). CML deposition was localized in the small intramyocardial arteries in endothelial cells and smooth muscle cells, but not in cardiomyocytes. These arteries did not show morphological abnormalities. The intensity of staining between arteries at the epicardial, midcardial and endocardial side did not vary significantly within patients. In renal tissues, CML staining was most prominent in tubules and in atherosclerotic vessels, without differences in intensity between controls and diabetic patients. In non-infected lungs, no CML was detected. In conclusion, CML adducts are abundantly present in small intramyocardial arteries in the heart tissue of diabetic patients. The accumulation of CML in diabetic hearts may contribute to the increased risk of heart failure in hyperglycaemia.
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PMID:Increased accumulation of the glycoxidation product Nepsilon-(carboxymethyl)lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody. 1516 55

Angiotensin-converting enzyme and neutral endopeptidase (EC 3.4.24.11; neprilysin) are metallopeptidases present on the endothelium that metabolize bradykinin. Inhibitors of angiotensin-converting enzyme potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. Combined angiotensin-converting enzyme and neutral endopeptidase inhibition may have additional beneficial cardiovascular effects mediated through bradykinin potentiation. We investigated the effects of local neutral endopeptidase inhibition on the vascular actions of bradykinin in heart failure patients maintained on chronic angiotensin-converting enzyme inhibition. Ten patients received intrabrachial infusion of thiorphan (30 nmol/min), a neutral endopeptidase inhibitor, in a randomized double-blind placebo-controlled crossover trial. Thiorphan was coinfused with Lys-des-Arg9-bradykinin (1 to 10 nmol/min), bradykinin (30 to 300 pmol/min), atrial natriuretic peptide (10 to 100 pmol/min), and sodium nitroprusside (2 to 8 mug/min). Bradykinin, atrial natriuretic peptide, and sodium nitroprusside caused dose-dependent vasodilatation (peak blood flow 14.4+/-2.2, 3.6+/-0.6, and 8.6+/-1.3 mL per 100 mL/min, respectively; P<0.0001). Bradykinin caused dose-dependent increases in tissue plasminogen activator antigen and activity (peak concentration 31.8+/-3.4 ng/mL and 21.9+/-7.6 IU/mL, respectively; P<0.001) and estimated antigen and activity release (peak release 152+/-46 ng per 100 mL/min and 154+/-22 IU/100 mL/min, respectively; P<0.005). Compared with placebo, thiorphan augmented bradykinin-mediated vasodilatation (1.4-fold; P<0.0001) and net tissue plasminogen activator release (1.5-fold; P<0.005). Neutral endopeptidase contributes to bradykinin metabolism in heart failure patients maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the clinical effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition, including the greater vasodepressor effect observed with combined therapy when compared with angiotensin-converting enzyme inhibition alone.
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PMID:Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. 1549 33

Semicarbazide-sensitive amine oxidase (SSAO) resides on the vascular endothelium and smooth muscle cell surface and is capable of deaminating short chain aliphatic amines and producing toxic aldehydes and hydrogen peroxide. The enzyme, also known as a vascular adhesion protein-1, is involved in the inflammation process. This intriguing protein with dual functions is increased in the serum of diabetic and heart failure patients. In the present study we assessed the involvement of SSAO in a lipopolysaccharide-induced pulmonary inflammation model using transgenic mice that overexpress human vascular adhesion protein-1. Overexpression of SSAO activity increased the formation of protein-formaldehyde deposits in tissues. Lysine residues of proteins were the primary targets for cross-linkage with formaldehyde derived from deamination of methylamine. Lipo-polysaccharide-induced increases in inflammatory cells in the bronchoalveolar lavage (BAL) fluid were significantly higher in the transgenic than in the nontransgenic mice. BAL cell counts were also higher in the untreated transgenic than in nontransgenic mice. Blocking SSAO activity with a selective inhibitor significantly reduced the number of neutrophils as well as levels of macrophage inflammatory protein-1alpha, granulocyte colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 in the BAL fluid. Inhalation of methylamine also increased BAL neutrophil counts. Together, these results suggest a role for SSAO-mediated deamination in pulmonary inflammation.
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PMID:Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in lipopolysaccharide-induced pulmonary inflammation. 1650 87

Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, beta(1) adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.
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PMID:Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. 1712 54

Cardiac hypertrophy is associated with a dramatic change in the gene expression profile of cardiac myocytes. Many genes important during development of the fetal heart but repressed in the adult tissue are reexpressed, resulting in gross physiological changes that lead to arrhythmias, cardiac failure, and sudden death. One transcription factor thought to be important in repressing the expression of fetal genes in the adult heart is the transcriptional repressor REST (repressor element 1-silencing transcription factor). Although REST has been shown to repress several fetal cardiac genes and inhibition of REST function is sufficient to induce cardiac hypertrophy, the molecular mechanisms employed in this repression are not known. Here we show that continued REST expression prevents increases in the levels of the BNP (Nppb) and ANP (Nppa) genes, encoding brain and atrial natriuretic peptides, in adult rat ventricular myocytes in response to endothelin-1 and that inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter-proximal regions of these genes. Furthermore, using deletions of individual REST repression domains, we show that the combined activities of two domains of REST are required to efficiently repress transcription of the Nppb gene; however, a single repression domain is sufficient to repress the Nppa gene. These data provide some of the first insights into the molecular mechanism that may be important for the changes in gene expression profile seen in cardiac hypertrophy.
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PMID:The repressor element 1-silencing transcription factor regulates heart-specific gene expression using multiple chromatin-modifying complexes. 1737 49

In animal models of cardiac disease and in human congestive heart failure, expression of angiotensin-converting enzyme (ACE) is upregulated in the failing heart and has been associated with disease progression leading to cardiac failure and fibrosis. To develop probes for imaging ACE expression, a series of di(2-pyridylmethyl)amine (D) chelates capable of binding M(CO)3+ (M = technetium, rhenium) was conjugated to lisinopril by acylation of the epsilon-amine of the lysine residue with a series of di(2-pyridylmethylamino)alkanoic acids where the distance of the chelator from the lisinopril core was investigated by varying the number of methylene spacer groups to produce di(2-pyridylmethyl)amine(Cx)lisinopril analogs: D(C4)lisinopril, D(C5)lisinopril, and D(C8)lisinopril. The inhibitory activity of each rhenium complex was evaluated in vitro against purified rabbit lung ACE and was shown to vary directly with the length of the methylene spacer: Re[D(C8)lisinopril], inhibitory concentration of 50% (IC50) = 3 nM; Re[D(C5)lisinopril], IC50 = 144 nM; and Re[D(C4)lisinopril], IC50 = 1,146 nM, as compared with lisinopril, IC50 = 4 nM. The in vivo specificity for ACE was determined by examining the biodistribution of the 99mTc-[D(C8)lisinopril] analog in rats with and without pretreatment with unlabeled lisinopril. Uptake in the lungs, a tissue that constitutively expresses ACE, was 15.2 percentage injected dose per gram at 10 min after injection and was dramatically reduced by pretreatment with lisinopril, supporting ACE-mediated binding in vivo. Planar anterior imaging analysis of 99mTc-[D(C8)lisinopril] corroborated these data. Thus, high-affinity 99mTc-labeled ACE inhibitor has been designed with potency similar to that of lisinopril and has been demonstrated to specifically localize to tissues that express ACE in vivo. This agent may be useful in monitoring ACE as a function of disease progression in relevant diseases such as heart failure.
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PMID:Synthesis and evaluation of a series of 99mTc(CO)3+ lisinopril complexes for in vivo imaging of angiotensin-converting enzyme expression. 1848 87

Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.
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PMID:Vascular B1 kinin receptors in patients with congestive heart failure. 1903 23

Epigenetic alterations are implicated in the development of cardiac hypertrophy and heart failure, but little is known of which epigenetic changes in which regions of the genome play such a role. We now show that trimethylation of histone H3 on lysine-4 (K4TM) or lysine-9 (K9TM) is markedly affected in cardiomyocytes in association with the development of heart failure in a rat disease model. High-throughput pyrosequencing performed with ChIP products for K4TM or K9TM prepared from human left ventricular tissue with retained or damaged function also revealed that protein-coding genes located in the vicinity of K4TM marks differ between functional and disabled myocytes, yet both sets of genes encode proteins that function in the same signal transduction pathways for cardiac function, indicative of differential K4TM marking during the development of heart failure. However, K9TM mark-profile was less dependent on the disease status compared to that of K4TM. Our data collectively reveal global epigenetic changes in cardiac myocytes associated with heart failure.
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PMID:Genome-wide histone methylation profile for heart failure. 1907 33

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