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)

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

Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOX-mediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function.
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PMID:Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. 2047 64

Cardiac failure is a leading cause of age-related death, though its root cause remains unknown. Mounting evidence implicates a decline in mitochondrial function due to increased opening of the mitochondrial permeability transition pore (mPTP). Here we report that the NAD+-dependent deacetylase SIRT3 deacetylates the regulatory component of the mPTP, cyclophilin D (CypD) on lysine 166, adjacent to the binding site of cyclosporine A, a CypD inhibitor. Cardiac myocytes from mice lacking SIRT3 exhibit an age-dependent increase in mitochondrial swelling due to increased mPTP opening, a phenotype that is rescued by cyclosporine A. SIRT3 knockout mice show accelerated signs of aging in the heart including cardiac hypertrophy and fibrosis at 13 months of age. SIRT3 knockout mice are also hypersensitive to heart stress induced by transverse aortic constriction (TAC), as evidenced by cardiac hypertrophy, fibrosis, and increased mortality. Together, these data show for the first time that SIRT3 activity is necessary to prevent mitochondrial dysfunction and cardiac hypertrophy during aging and shed light on new pharmacological approaches to delaying aging and treating diseases in cardiac muscle and possibly other post-mitotic tissues.
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PMID:Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. 2124 76

In recent years, protein lysine acetylation has emerged as a prominent and conserved regulatory posttranslational modification that is abundant on numerous enzymes involved in the processes of intermediary metabolism. Well-characterized mitochondrial processes of carbon utilization are enriched in acetyl-lysine modifications. Although seminal discoveries have been made in the basic biology of mitochondrial acetylation, an understanding of how acetylation states influence enzyme function and metabolic reprogramming during pathological states remains largely unknown. This paper will examine our current understanding of eukaryotic acetate metabolism and present recent findings in the field of mitochondrial acetylation biology. The implications of mitochondrial acetylation for the aging process will be discussed, as well as its potential implications for the unique and localized metabolic states that occur during the aging-associated conditions of heart failure and cancer growth.
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PMID:Mitochondrial acetylation and diseases of aging. 2143 90

L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.
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PMID:L-carnitine--metabolic functions and meaning in humans life. 2156 31

Histone H3 lysine 4 (H3K4me) methyltransferases and their cofactors are essential for embryonic development and the establishment of gene expression patterns in a cell-specific and heritable manner. However, the importance of such epigenetic marks in maintaining gene expression in adults and in initiating human disease is unclear. Here, we addressed this question using a mouse model in which we could inducibly ablate PAX interacting (with transcription-activation domain) protein 1 (PTIP), a key component of the H3K4me complex, in cardiac cells. Reducing H3K4me3 marks in differentiated cardiomyocytes was sufficient to alter gene expression profiles. One gene regulated by H3K4me3 was Kv channel-interacting protein 2 (Kcnip2), which regulates a cardiac repolarization current that is downregulated in heart failure and functions in arrhythmogenesis. This regulation led to a decreased sodium current and action potential upstroke velocity and significantly prolonged action potential duration (APD). The prolonged APD augmented intracellular calcium and in vivo systolic heart function. Treatment with isoproterenol and caffeine in this mouse model resulted in the generation of premature ventricular beats, a harbinger of lethal ventricular arrhythmias. These results suggest that the maintenance of H3K4me3 marks is necessary for the stability of a transcriptional program in differentiated cells and point to an essential function for H3K4me3 epigenetic marks in cellular homeostasis.
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PMID:Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes. 2164 17

Defective tissue regeneration is thought to contribute to several human diseases, including neurodegenerative disorders, heart failure and various lung diseases. Boosting the regenerative capacity has been suggested a possible therapeutic approach. Methods to metabolically label newly synthesized proteins in vivo with stable isotopic forms of amino acids holds promise for the study of protein turnover and tissue regeneration that are fundamental to the sustained life of all organisms. Here, we used the "stable isotope labeling with amino acids in cell culture" (SILAC) approach to explore normal protein turnover and tissue regeneration in adult zebrafish. The ratio of labeled and unlabeled proteins/peptides in specific organs of zebrafish fed a SILAC diet containing (13)C(6)-labeled lysine was determined by liquid chromatography and tandem mass spectrometry. Labeling was highest in tissues with high regenerative capacity, including intestine, liver, and fin, whereas brain and heart displayed the lowest labeling. Proteins with high degree of labeling were mainly involved in catalytic or transport activity pathways. The technique also verified increased protein synthesis during regeneration of the caudal fin following amputation. This newly developed SILAC zebrafish model constitutes a novel tool to analyze tissue regeneration in an animal model amenable to genetic and pharmacologic manipulation.
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PMID:SILAC zebrafish for quantitative analysis of protein turnover and tissue regeneration. 2189 6


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