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)

Chronic Chagas' disease cardiomyopathy is a leading cause of congestive heart failure in Latin America, affecting more than 3 million people. Chagas' cardiomyopathy is more aggressive than other cardiomyopathies, but little is known of the molecular mechanisms responsible for its severity. We characterized gene expression profiles of human Chagas' cardiomyopathy and dilated cardiomyopathy to identify selective disease pathways and potential therapeutic targets. Both our customized cDNA microarray (Cardiochip) and real-time reverse transcriptase-polymerase chain reaction analysis showed that immune response, lipid metabolism, and mitochondrial oxidative phosphorylation genes were selectively up-regulated in myocardial tissue of the tested Chagas' cardiomyopathy patients. Interferon (IFN)-gamma-inducible genes represented 15% of genes specifically up-regulated in Chagas' cardiomyopathy myocardial tissue, indicating the importance of IFN-gamma signaling. To assess whether IFN-gamma can directly modulate cardio-myocyte gene expression, we exposed fetal murine cardiomyocytes to IFN-gamma and the IFN-gamma-inducible chemokine monocyte chemoattractant protein-1. Atrial natriuretic factor expression increased 15-fold in response to IFN-gamma whereas combined IFN-gamma and monocyte chemoattractant protein-1 increased atrial natriuretic factor expression 400-fold. Our results suggest IFN-gamma and chemokine signaling may directly up-regulate cardiomyocyte expression of genes involved in pathological hypertrophy, which may lead to heart failure. IFN-gamma and other cytokine pathways may thus be novel therapeutic targets in Chagas' cardiomyopathy.
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PMID:Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy. 1604 18

The immature and mature heart differ from each other in terms of excitability, action potential properties, contractility, and relaxation. This includes upregulation of repolarizing K(+) currents, an enhanced inward rectifier K(+) (Kir) current, and changes in Ca(2+), Na(+), and Cl(-) currents. At the molecular level, the developmental regulation of ion channels is scantily described. Using a large-scale real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay, we performed a comprehensive analysis of ion channel transcript expression during perinatal development in the embryonic (embryonic day 17.5), neonatal (postnatal days 1-2), and adult Swiss-Webster mouse hearts. These data are compared with publicly available microarray data sets (Cardiogenomics project). Developmental mRNA expression for several transcripts was consistent with the published literature. For example, transcripts such as Kir2.1, Kir3.1, Nav1.5, Cav1.2, etc. were upregulated after birth, whereas others [e.g., Ca(2+)-activated K(+) (KCa)2.3 and minK] were downregulated. Cl(-) channel transcripts were expressed at higher levels in immature heart, particularly those that are activated by intracellular Ca(2+). Defining alterations in the ion channel transcriptome during perinatal development will lead to a much improved understanding of the electrophysiological alterations occurring in the heart after birth. Our study may have important repercussions in understanding the mechanisms and consequences of electrophysiological alterations in infants and may pave the way for better understanding of clinically relevant events such as congenital abnormalities, cardiomyopathies, heart failure, arrhythmias, cardiac drug therapy, and the sudden infant death syndrome.
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PMID:Large-scale analysis of ion channel gene expression in the mouse heart during perinatal development. 1698 3

Together, the limited capacity for regenerative growth in cardiac muscle after injury and the prevalence of ongoing sporadic cell death due to apoptosis in chronic heart failure states pose one of the paramount challenges in heart failure therapeutics. In adults, the unique self-renewal potential of progenitor/stem cells is associated with telomerase reverse transcriptase (TERT), an RNA-dependent DNA polymerase that maintains the lariat-like loop capping chromosome ends. We have identified telomere uncapping, mediated by down-regulation of telomere repeat-binding factor 2 (TRF2) as a novel trigger of cell death in human dilated cardiomyopathy. Conversely, we identified a residual TERT+ population in adult myocardium, as a potential source of cardiac progenitor cells. Residual TERT expression was localized to cells expressing stem cell antigen 1 (Sca1). Cardiac-resident Sca1+ cells lack haematopoietic stem cell markers and transcripts for cardiac structural genes, yet express many cardiogenic transcription factors. If given intravenously to mice just after ischemia-reperfusion injury, cardiac Sca1+ cells home selectively to injured myocardium and differentiate spontaneously in situ.
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PMID:Dual roles of telomerase in cardiac protection and repair. 1701 17

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Diabetic cardiomyopathy (DCM) is increasingly recognized as a major contributor to diastolic dysfunction and heart failure in diabetes, but its molecular basis has remained obscure, in part because of its multifactorial origins. Here we employed comparative transcriptomic methods with quantitative verification of selected transcripts by reverse transcriptase quantitative PCR to characterize the molecular basis of DCM in rats with streptozotocin-induced diabetes of 16-wk duration. Diabetes caused left ventricular disease that was accompanied by significant changes in the expression of 1,614 genes, 749 of which had functions assignable by Gene Ontology classification. Genes corresponding to proteins expressed in mitochondria accounted for a disproportionate number of those whose expression was significantly modified in DCM, consistent with the idea that the mitochondrion is a key target of the pathogenic processes that cause myocardial disease in diabetes. Diabetes also induced global perturbations in the expression of genes regulating cardiac fatty acid metabolism, whose dysfunction is likely to play a key role in the promotion of oxidative stress, thereby contributing to the pathogenesis of diabetic myocardial disease. In particular, these data point to impaired regulation of mitochondrial beta-oxidation as central in the mechanisms that generate DCM pathogenesis. This study provides a comprehensive molecular snapshot of the processes leading to myocardial disease in diabetes.
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PMID:Transcriptomic analysis of the cardiac left ventricle in a rodent model of diabetic cardiomyopathy: molecular snapshot of a severe myocardial disease. 1706 50

Sodium current I(Na) plays an important role in the pacemaker activity of the sinoatrial node (SAN). However, expression profiles of corresponding sodium channel subunits in normal SAN remain unclear. And little is known about expression alteration of sodium channel in SAN under heart failure (HF) condition. We assessed SAN function and expression of Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6, and Nav1.7 in sham-operated rats and rats subjected to abdominal arteriovenous shunt (volume overload)-induced HF. Immunohistochemistry, Western blot, and quantitative real-time reverse transcriptase PCR analysis were used to quantify sodium channel subunit protein and mRNA expression in the SAN. Intrinsic heart rate declined and sinus node recovery time was prolonged in HF rats, indicating suppressed SAN pacemaker function. In rat SAN, Nav1.1 and Nav1.6 were the primary subunits, Nav1.5 and Nav1.7 were weakly expressed, and Nav1.2 and Nav1.3 were not found to be present. HF significantly decreased SAN sodium channel expression at both the protein and mRNA levels (Nav1.1 by 61 and 71%, Nav1.6 by 49 and 46%, respectively). In conclusion, Nav1.1 and Nav1.6 are the dominant subunits in rat SAN, and downregulation of Nav1.1 and Nav1.6 expression contributes to HF-induced SAN dysfunction. These findings provide additional information about molecular basis of disease-related impairment of SAN function.
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PMID:Downregulation of neuronal sodium channel subunits Nav1.1 and Nav1.6 in the sinoatrial node from volume-overloaded heart failure rat. 1727 63

Regular exercise is beneficial to cardiovascular health. We tested whether mild voluntary exercise training modifies key myocardial parameters [ventricular mass, intracellular calcium ([Ca2+]i) handling and the response to beta-adrenoceptor (beta-AR) stimulation] in a manner distinct from that reported for beneficial, intensive training and pathological hypertrophic stimuli. Female rats performed voluntary wheel-running exercise for 6-7 weeks. The mRNA expression of target proteins was measured in left ventricular tissue using real-time reverse transcriptase-polymerase chain reaction. Simultaneous measurement of cell shortening and [Ca2+]i transients were made in single left ventricular myocytes and the inotropic response to beta1- and beta2-AR stimulation was measured. Voluntary exercise training resulted in cardiac hypertrophy, the heart weight to body weight ratio being significantly greater in trained compared with sedentary animals. However, voluntary exercise caused no significant alteration in the size or time course of myocyte shortening and [Ca2+]i transients or in the mRNA levels of key proteins that regulate Ca2+ handling. The positive inotropic response to beta1-AR stimulation and the level of beta1-AR mRNA were unaltered by voluntary exercise but both mRNA levels and inotropic response to beta2-AR stimulation were significantly reduced in trained animals. The beta2-AR inotropic response was restored by exposure to pertussis toxin. We propose that in contrast to pathological stimuli and to beneficial, intense exercise training, modulation of Ca2+ handling is not a major adaptive mechanism in the response to mild voluntary exercise. In addition, and in a reversal of the situation seen in heart failure, voluntary exercise training maintains the beta1-AR response but reduces the beta2-AR response. Therefore, although voluntary exercise induces cardiac hypertrophy, there are distinct differences between its effects on key myocardial regulatory mechanisms and those of hypertrophic stimuli that eventually cause cardiac decompensation.
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PMID:Voluntary exercise-induced changes in beta2-adrenoceptor signalling in rat ventricular myocytes. 1848 15

Apolipoprotein D (Apo D) is reported to be in close association with developing and mature blood vessels, and involved in enhanced smooth muscle cell migration after injury. This study was designed to clarify the expression pattern of Apo D and the possibility of Apo D as a new marker in human end-stage heart failure. Individual RNA samples obtained from independent left ventricular tissue of six heart failure patients derived from cardiomyopathies of different aetiologies during cardiac transplantation and six non-failing control subjects were hybridized to the gene microarray containing, in total, 35 000 well-characterized Homo sapiens genes. Apo D was one of the highly expressed genes (3.3-fold upregulated) detected by microarray, which was further confirmed by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) (5.88-fold upregulated) in failing hearts compared with non-failing hearts. Both Western blotting and immunohistochemistry analyses also demonstrated the higher levels of Apo D protein in failing hearts. Importantly, we observed elevated levels of plasma Apo D in heart failure patients compared with non-failing control subjects. We demonstrated, for the first time to our knowledge, that Apo D was highly expressed in the mRNA and protein levels in human failing hearts compared with non-failing hearts. Furthermore, our finding of elevated plasma Apo D levels in patients with heart failure provides clues that Apo D may act not only as a cardiac molecular marker but also as a circulating biomarker in patients with heart failure.
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PMID:Apolipoprotein D as a novel marker in human end-stage heart failure: a preliminary study. 3225 39

To investigate the changes of inducible cAMP early repressor (ICER) and phosphodiesterase 3A in rats after myocardial infarction and to evaluate the beneficial effects of valsartan on cardiac function and ventricular remodeling. Rats were split into four groups: sham-operation group, pre-myocardial infarction group (valsartan administration 2 weeks before myocardial infarction), post-myocardial infarction group (valsartan administration after myocardial infarction) and myocardial infarction group (vehicle after myocardial infarction). Echocardiograph and hemodynamic data were measured and cardiocyte apoptosis was estimated by TUNEL staining. ICER, cAMP response element binding protein (CREB), phosphodiesterase 3A and Bcl-2 mRNA expression levels were assayed by real-time reverse transcriptase polymerase chain reaction and protein expression was measured using immunoblot analysis. ICER and CREB mRNA expression in the myocardial infarction group were higher and phosphodiesterase 3A and Bcl-2 mRNA expression were lower than the sham-operation group (Ps<0.01). Following the improvement of cardiac function and ventricular remodeling, ICER and CREB mRNA in pre- and post- myocardial-infarction groups were down-regulated, and phosphodiesterase 3A and Bcl-2 mRNA were up-regulated (P<0.05). The changes brought on by valsartan pre-myocardial infarction were stronger than post-myocardial infarction (P<0.05). These data suggest that there is a phosphodiesterase 3A-ICER positive-feedback loop leading to myocyte apoptosis and ongoing development of heart failure after myocardial infarction. Maintaining the function of phosphodiesterase 3A or reducing ICER may be an effective way to prevent myocardium apoptosis and heart dysfunction. Valsartan can ameliorate ventricular remodeling and heart failure by inhibiting the expression of ICER and increasing the expression of phosphodiesterase 3A.
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PMID:Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction. 1902 36

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.
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PMID:Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. 2012 77

ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.
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PMID:Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters. 2022 53


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