Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.5 (RNase)
 17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic dilated cardiomyopathy is associated with derangement of myocardial sarcoplasmic Ca-homeostasis and energy production. The molecular mechanism for these changes is unknown. Accordingly, we used genetic and experimentally-induced models of canine dilated cardiomyopathy and tested the hypothesis that these metabolic changes resulted from altered gene expression, as indicated by mRNA content. We studied dilated cardiomyopathy occurring naturally (n = 9) in Doberman pinschers, and in dogs subjected to rapid ventricular pacing (n = 5), in comparison with normal dogs (n = 9). We determined content and integrity of mRNA's using Northern and slot blotting, and measured activities of their translated product for the Ca-release channel and Ca-ATPase of sarcoplasmic reticulum, lactate dehydrogenase of glycolysis, citrate synthase of the tricarboxylic acid cycle, and for myoglobin, ATP-synthetase and the adenine nucleotide transporter, which are integral in oxidative phosphorylation. We found that, whereas both mRNA content and enzyme activity for markers of Ca-cycling, glycolysis, and oxidative phosphorylation were downregulated (20-80%) in dilated cardiomyopathy, they were upregulated (10-15%) for tricarboxylic acid cycling and for ribosomal RNA. RNA from cardiomyopathic tissue was up to 50% more degraded than for normal hearts in association with a 150% increase in ribonuclease activity. Downregulation of the Ca-cycle was asymmetric, with the Ca-channel being 65% more affected than the Ca-ATPase. This work supports the general paradigm that transcriptional and translational responses to pathophysiology are major determinants of the metabolic response seen in cardiac failure.
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PMID:Myocardial mRNA content and stability, and enzyme activities of Ca-cycling and aerobic metabolism in canine dilated cardiomyopathies. 777 66

In human heart failure beta-adrenergic receptors are downregulated which contributes to the reduced responsiveness to positive inotropic beta-agonists in the diseased heart. The present study addressed the question whether the number of beta-adrenergic receptors in the failing human heart is regulated at the level of the mRNA and whether the absolute steady-state levels of subtype-specific mRNAs mirror the expression of receptor-subtype proteins in human heart. In a collaborative effort, two different and independent methods, performed in two independent laboratories, reverse transcription followed by polymerase chain reaction (RT-PCR) and RNase protection assays, were used to determine the absolute steady-state levels of beta 1- and beta 2-adrenergic receptor mRNAs in control (NF) and in failing human hearts. As determined by quantitative RT-PCR the beta 1-mRNA was significantly reduced from 0.98 +/- 0.12 (n = 10) to 0.49 +/- 0.11 pg/microgram total RNA in dilated cardiomyopathy (dCMP, n = 7) and to 0.40 +/- 0.11 pg/microgram total RNA in ischemic cardiomyopathy (iCMP, n = 8). The steady-state levels of mRNA specific for beta 2-adrenergic receptors also tended to be decreased but without reaching significance (NF: 0.16 +/- 0.05, dCMP: 0.11 +/- 0.03, iCMP: 0.13 +/- 0.04 pg/microgram total RNA). RNase protection assays revealed similar values. beta 1-mRNA was found to be significantly reduced from 1.22 +/- 0.22 in NF (n = 10) to 0.63 +/- 0.14 pg/microgram total RNA in dCMP (n = 5) and to 0.52 +/- 0.1 pg/microgram total RNA in iCMP (n = 8). The beta 2-mRNA also tended to be lower in dCMP and in iCMP as compared to NF but again without reaching significance (NF: 0.14 +/- 0.02, dCMP: 0.099 +/- 0.02, iCMP 0.107 +/- 0.02 pg/microgram total RNA). This is the first study to demonstrate in parallel by two different methods performed independently in two laboratories that the ratio of beta 1- and beta 2-adrenergic receptor densities in the left ventricle of the normal human heart of about 80/20 is closely related to the absolute steady state concentrations of their specific mRNA. In addition, the magnitude of the decrease in mRNA-levels of beta 1- and beta 2-adrenergic receptors in the failing human heart closely correlates with the decrease of the respective receptor proteins. These data suggest that the predominant regulation of beta-adrenergic receptors occurs at the mRNA level.
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PMID:Differential regulation of mRNA specific for beta 1- and beta 2-adrenergic receptors in human failing hearts. Evaluation of the absolute cardiac mRNA levels by two independent methods. 874 9

The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.
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PMID:Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure. 959 2

We have previously reported that mice with cardiac-specific overexpression of tumor necrosis factor (TNF)- alpha develop myocardial inflammation, cardiac hypertrophy, and dilated cardiomyopathy. TNF- alpha is reported to induce apoptosis in cultured cardiac myocytes. To investigate the role of apoptosis in this transgenic model, wild-type controls (WT) and transgenic mice (TG) at the age of 1, 8, and 40 weeks were analyzed. Increased incidence of apoptosis in TG was indicated by DNA laddering. TUNEL assays revealed that the frequencies of apoptotic cells were increased in the TG myocardium at all ages. However, as revealed by histochemical and immunofluorescent methods, most of the apoptotic cells appeared to be non-myocytes even in the mice with overt congestive heart failure. To elucidate the signaling pathways responsible for TNF- alpha induced apoptosis, expression of apoptosis-related genes were evaluated by multi-probe RNase protection assays. Transcripts for death-domain-related proteins, including TNFR1, Fas, FADD, TRADD, and RIP, were constitutively expressed in WT and upregulated in the TG myocardium. Expression of caspase-1 through -8 was also enhanced in TG. While both anti- and pro-apoptotic Bcl-2 family genes were constitutively expressed in WT, TNF- alpha overexpression strongly induced anti-apoptotic A1 in the myocardium. Furthermore, TNF- alpha overexpression activated NF- kappa B, a mediator of anti-apoptotic pathways, in the myocardium. Thus, overexpression of TNF- alpha activated both anti- and pro-apoptotic pathways in the myocardium, resulting in an increase of apoptosis, primarily in non-myocytes. These results suggest that TNF- alpha by itself is not sufficient to induce apoptosis in cardiac myocytes in vivo.
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PMID:Overexpression of tumor necrosis factor- alpha activates both anti- and pro-apoptotic pathways in the myocardium. 1143 39

The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMR-expressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2- to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum- and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum- and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.
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PMID:Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor. 1149 2

Chronic myocardial ischemia is the leading cause of impaired myocardial contractility and heart failure. To identify differentially expressed genes in human ischemic cardiomyopathy (ICM), we constructed a subtracted cDNA library using specimens of ICM compared to normal human heart. Among 100 randomly sequenced clones, seven sequences represented recently identified candidate genes for differential expression in cardiac hypertrophy. A further clone without a known hypertrophy-association coded for the adhesion molecule NCAM(CD56). RNase protection assay, immunohistochemistry, and Western blotting revealed strong overexpression of NCAM(CD56) in all hearts with ICM (n = 14) compared to normal hearts (n = 8), whereas in congestive cardiomyopathy (CCM) (n = 8), hypertrophic obstructive cardiomyopathy (n = 2), myocarditis (n = 4), and sarcoidosis (n = 2), at most slight overexpression of NCAM(CD56) was observed. NCAM(CD56) overexpression abnormally involved the whole cell membrane and the cytoplasma of cardiomyocytes only inside and adjacent to ischemia-induced cardiac scars. Normal or hypertrophic fibers at a distance from ischemic scars were devoid of NCAM overexpression. Identical alterations were observed in an experimental rat ICM model, but not in normal nor in spontaneously hypertensive rat hearts. In search of NCAM(CD56)-related transcription factors we found RUNX1(AML1) up-regulation in ICM and detected RUNX1(AML1) binding within the NCAM(CD56) promoter by electromobility shift assay. We concluded that strong overexpression of NCAM(CD56) and RUNX1(AML1) is a constant and characteristic feature of cardiomyocytes within or adjacent to scars in ICM.
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PMID:NCAM(CD56) and RUNX1(AML1) are up-regulated in human ischemic cardiomyopathy and a rat model of chronic cardiac ischemia. 1293 48