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)

Recent studies have shown that intracellular Ca2+ handling is abnormal in the myocardium of patients with end-stage heart failure. Muscles from the failing hearts showed a prolonged Ca2+ transient and a diminished capacity to restore a low resting Ca2+ level during diastole. Accordingly, we examined whether this defect in Ca2+ transport function is due to alterations in sarcoplasmic reticulum gene expression. We determined the messenger RNA (mRNA) levels of sarcoplasmic reticulum Ca2+ transport proteins in failing human hearts from 17 cardiac transplant recipients with a diagnosis of dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The expression levels of each mRNA were compared with each other and then correlated with that of atrial natriuretic factor (ANF) mRNA in the failing ventricle. The mRNA levels for the calcium release channel (ryanodine receptor, RYR2), Ca2+ uptake pump (Ca(2+)-ATPase, SERCA2 isoform), and phospholamban differed significantly between heart samples but showed an inverse relation with that of ventricular ANF mRNA. In contrast, calsequestrin mRNA levels remained unchanged in these failing hearts. In addition, beta-myosin and alpha-cardiac actin mRNA levels also showed an inverse relation with ANF mRNA levels. These changes were observed in both right and left ventricles of hearts with congestive heart failure due to dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The results are consistent with the hypothesis that abnormal calcium handling in the sarcoplasmic reticulum of failing hearts is due to the altered expression of the genes encoding sarcoplasmic reticulum proteins.
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PMID:Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. 841 95

Recent studies have implicated angiotensin II (angiotensin) in the pathogenesis of cardiac hypertrophy and heart failure. Heart failure is associated with alterations in intracellular Ca2+ movements mediated by sarcolemmal (SL) and sarcoplasmic reticular (SR) membranes in cardiac myocytes. As it was suspected that alteration gene expression of proteins responsible for controlling transmembrane Ca2+ fluxes may contribute to loss of Ca2+ homeostasis in failing hearts, we undertook a study of the effect of angiotensin on the expression of some target genes in the myocardium. Specifically, we tested the effect of angiotensin on mRNA abundance of cardiac Ca(2+)-transport genes including SL Na+/Ca2+ exchange (EX), SR ryanodine receptor (RYR), and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). The mRNA abundance of target gene was assessed by Northern blot assay in (i) direct hormonal stimulation of cultured isolated neonatal and adult rat myocytes and (ii) adult rat hearts after implantation of osmotic mini-pumps for delivery of hormone. In all experiments, Northern blot data were normalized using cDNA (Glyceraldehyde 3-phosphate dehydrogenase signal, GAPDH) hybridization to RNA samples. The results indicate that the ratios of EX/GAPDH, RYR/GAPDH, and SERCA2/GAPDH signals were decreased by 51.6%, 55.0%, and 49.4% respectively after neonatal cardiac myocytes were treated (24 h) with 10(-7) M angiotensin. These decreases were blocked completely by treatment with angiotensin subtype 1 (AT1) receptor antagonist (losartan), whereas angiotensin subtype 2 (AT2) receptor antagonist (PD123319) treatment had no effect on the angiotensin-mediated decrease in target gene mRNA abundance. In contrast, angiotensin had no effect on EX, RYR nor SERCA2 gene mRNA abundance in cultured adult myocytes. In a separate series of experiments wherein adult male Sprague-Dawley rats were infused with different dose of angiotensin for 3 days via osmotic mini-pump, we did not detect any alterations in mRNA abundance of cardiac EX/GAPDH, RYR/GAPDH or SERCA/GAPDH genes in either left or right ventricular samples. Thus our results indicate that, in neonatal rat myocytes, angiotensin affects SL and SR calcium transport gene expression by direct agonism of AT1-receptors. As the infusion of low and high dose angiotensin did not affect the expression of target genes in adult hearts, we suggest that the mechanisms for transduction of the angiotensin signaling in neonatal and adult myocytes may be different and may depend on the stage of development. We conclude that regulation of myocardial Ca(2+)-transport gene mRNA abundance by angiotensin may differ among neonatal and adult animals. Nonetheless, our finding with respect to neonatal preparation led us to believe that in neonatal myocytes, the mRNA abundance of SL Na+/Ca2+ exchange, SR ryanodine receptor, and SR Ca(2+)-ATPase are all decreased in response to stimulation by angiotensin.
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PMID:Altered mRNA abundance of calcium transport genes in cardiac myocytes induced by angiotensin II. 876 48

Pressure overload on the heart is known to produce hypertrophy of cardiomyocytes and distinct changes in protein phenotype, including reduced expression of the gene for the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA2). In this study we have shown that the decrease in SERCA2 gene expression (normalized by poly(A)+ mRNA or 18 S rRNA) in rats with 8 wk of aortic constriction was prevented by treatment with etomoxir, an inhibitor of carnitine palmitoyltransferase 1. The reduction in steady-state mRNA levels for SR phospholamban (PLP) and Ca2+ release channel (CRC) in the pressure-overloaded animals was also prevented without any reduction in the extent of cardiac hypertrophy by treatment with etomoxir. Although no changes in mRNA levels for GAPDH were evident in rats with pressure overload, the expression of the alpha-skeletal actin was increased; this change was prevented by etomoxir. Similar beneficial effects of etomoxir treatment were also evident when the gene expression for SR SERCA2, PLP, and CRC in the hypertrophied heart was normalized with respect to mRNA for GAPDH. These results support the view that drugs such as etomoxir may increase the abundance of the mRNA for SR proteins in the hypertrophied heart and thus may prevent the transition of cardiac hypertrophy into heart failure.
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PMID:Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir. 883 44

The sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) plays a critical role in regulating Ca2+ movements in myocardium. In cardiac hypertrophy and human heart failure, the decrease in mRNA and protein levels of SERCA2 might account for the reduced diastolic Ca2+ re-uptake seen in these conditions. To investigate the regulation of human SERCA2 gene expression, an 18.6-kb human genomic clone that contains exons 1,2 and 3 of the SERCA2 gene has been isolated, and 13 kb of 5' upstream flanking sequence of which the proximal 2.5 kb of the promoter have been sequenced. Similar to the rabbit gene, the human SERCA2 promoter possesses a TATA-like box (-25 bp), a CAAT-box (-78 bp) and a number of consensus cis-regulatory elements including three Sp1 sites, a CACCC-box, and an OTF-1 binding sequence. No CArG box (present in the rabbit SERCA2 promoter) was identified in the human proximal promoter. Two putative thyroid response elements (TRE) are also present, suggesting that the human SERCA2 gene is also regulated by thyroid hormone as are the rat and rabbit genes. To study transcriptional activity of the human SERCA2 promoter in vitro, luciferase reporter plasmids containing a series of 5' deleted promoter constructs from -2577 bp to +170 bp were transfected into neonatal rat cardiomyocytes and C2C12 myotubes. The results suggest that: (a) the sequences from the transcription start site to -263 bp are necessary to obtain maximal transcriptional activity; (b) sequences from the transcription start site to -125 bp are essential for basal transcriptional activity; (c) at least one positive regulatory element is located between -263 bp and -125 bp; and (d) at least one negative regulatory element is present between -1741 bp and -412 bp.
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PMID:Molecular cloning and analysis of the human cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) gene promoter. 893 Aug 9

To determine whether reduced sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) (SERCA2) activity contributes to delayed myocardial relaxation during chronic left ventricular hypertrophy (LVH) progression, LVH was produced in rats by abdominal aortic coarctation. Systolic and diastolic functions were assessed in vivo 8 and 16 wk after surgery, and compositional alterations in LV myocardium [SERCA2 concentration, myosin heavy chain (MHC) isoenzymes, and tissue collagen] were correlated with the development of prolonged isovolumic relaxation and impaired cardiac performance over time. Myocardial relaxation was prolonged in 8-wk banded rats, despite normal isovolumic systolic function and LV end-diastolic pressure (LVEDP). No significant alterations in SERCA2 protein, beta-MHC, or fibrillar collagen levels were observed at this early time point. In contrast, LV SERCA2, beta-MHC, and fibrillar collagen concentrations were all significantly altered in 16-wk banded rats. These late compositional changes were associated with reduced cardiac performance, as manifested by a significant elevation in LVEDP (14 +/- 2 mmHg). The 34% decrease in SERCA2 protein was associated with reduced SR Ca2+ uptake and an even greater reduction (76%) in SERCA2 mRNA. SERCA2 mRNA levels were also significantly reduced to 43 +/- 10% of sham-operated rats 8 wk after banding, despite unchanged SERCA2 protein levels and normal SR Ca2+ uptake. These results argue against a significant contribution of SERCA2 downregulation to the subtle alterations in myocardial relaxation observed in compensated LVH. However, the early reduction in SERCA2 mRNA levels may serve as a molecular marker for impaired cardiac performance during the transition from compensated LVH to heart failure.
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PMID:Downregulation of sarcoplasmic reticulum Ca(2+)-ATPase during progression of left ventricular hypertrophy. 917 13

Phospholamban is a regulatory phosphoprotein which modulates the active transport of Ca2+ by the cardiac sarcoplasmic reticular Ca(2+)-ATPase enzyme (SERCA2) into the lumen of the sarcoplasmic reticulum. Phospholamban, which is a reversible inhibitor of SERCA2, represses the enzyme's activity, and this inhibition is relieved upon phosphorylation of phospholamban in response to beta-adrenergic stimulation. In this way, phospholamban is an important regulator of SERCA2-mediated myocardial relaxation during diastole. This report centers on the hypothesis that the relative levels of phospholamban: SERCA2 in cardiac muscle plays an important role in the muscle's overall contractility status. This hypothesis was tested by comparing the contractile parameters of: a) murine atrial and ventricular muscles, which differentially express phospholamban, and b) murine wild-type and phospholamban knock-out hearts. These comparisons revealed that atrial muscles, which have a 4.2-fold lower phospholamban: SERCA2 ratio than ventricular muscles, exhibited rates of force development and relaxation of tension, which were three-fold faster that these parameters for ventricular muscles. Similar comparisons were made via analyses of left-ventricular pressure development recorded for isolated, work-performing hearts from wild-type and phospholamban knock-out mice. In these studies, hearts from phospholamban knock-out mice, which were devoid of phospholamban, exhibited enhanced parameters of left-ventricular contractility in comparison to wild-type hearts. These results suggest that the relative phospholamban: SERCA2 ratio is critical in the regulation of myocardial contractility and alterations in this ratio may contribute to the functional deterioration observed during heart failure.
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PMID:The relative phospholamban and SERCA2 ratio: a critical determinant of myocardial contractility. 920 40

Congestive heart failure leads to skeletal muscle abnormalities, one of which is a prolongation of sarcoplasmic reticulum Ca2+ flux. The purpose of this study was to determine whether skeletal muscle of spontaneous hypertensive and heart failure rats have alterations in the expression of the sarcoplasmic (or endoplasmic) reticulum Ca(2+)-ATPase (SERCA) gene. Northern analysis revealed that SERCA1, the predominant skeletal muscle isoform, was decreased by 45%, 43%, and 58% in the tibialis anterior, plantaris, and diaphragm muscles, respectively. Ribonuclease protection assay showed that the decrease was due to the adult isoform, SERCA1a, with minor changes in the alternatively spliced neonatal isoform, SERCA1b. There was no change in SERCA1 mRNA levels in gastrocnemius muscles. No change was found in SERCA2a (cardiac/slow skeletal isoform) mRNA or protein levels or in SERCA2b (smooth muscle isoform), dihydropyridine receptor, or alpha-actin mRNA levels in diaphragm muscle. Northern blot and ribonuclease protection assays showed that SERCA2a decreased 61% in the heart while the alternatively spliced isoform, SERCA2b, decreased 27%. Western analysis of the tibialis anterior, diaphragm, and gastrocnemius muscles showed a decrease in SERCA1 protein levels by 46%, 64%, and 42%, respectively, whereas sarcoplasmic reticulum Ca(2+)-ATPase activity, a functional correlate of SERCA expression, was decreased by 38%, 38%, and 40% in the same muscles, SERCA2 protein expression decreased by 36% in the failing heart. Decreases in both mRNA and protein suggest pretranslational control of SERCA1 expression, whereas the lack of decreased SERCA1 mRNA in gastrocnemius muscle suggests translational regulation. The decreased SERCA1 protein expression in all muscles studied probably contributes to contractile abnormalities related to excitation-contraction coupling function in heart failure.
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PMID:Skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase gene expression in congestive heart failure. 935 44

The inositol 1,4,5-trisphosphate receptor (IP3R) is an endoplasmic reticular calcium release channel found in most cell types. Calcium signaling mediated by IP3Rs regulates a wide variety of physiological processes, including smooth muscle contraction, immune function, and fertility. We have focused on the role of the IP3R in programmed cell death and the regulation of IP3R levels in heart failure, a condition shown to be associated with cardiomyocyte apoptosis. During end-stage human heart failure, we have demonstrated that type 1 IP3R (IP3R1) mRNA and protein levels are up-regulated, in contrast to other cardiac calcium regulatory proteins, such as the type 2 ryanodine receptor (RYR2) and type IIa sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2), which are down-regulated. These data suggest that altered calcium channel expression may contribute to the defects in calcium homeostasis during heart failure. Furthermore, regulation of the IP3R may have implications for the survival of cardiac myocytes. Data from our laboratory have linked IP3R expression with susceptibility to apoptosis. IP3R-deficient T cells are resistant to apoptosis induced by dexamethasone, T cell receptor stimulation, ionizing radiation, and Fas. These findings suggest that intracellular calcium release via IP3Rs is a critical mediator of apoptosis. Thus the IP3R, which is up-regulated during human heart failure, may play a role in cardiomyocyte apoptosis and therefore in the pathophysiology of heart failure.
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PMID:Role of inositol 1,4,5-trisphosphate receptors in regulating apoptotic signaling and heart failure. 947 44

In mammalian myocardium, relaxation is mainly triggered by the reuptake of calcium from the cytosol to the lumen of the sarcoplasmic reticulum (SR) through the cardiac isoform of the sarco(endo)plasmic reticulum calcium ATPase, SERCA2a. Relaxation abnormalities related to deficient SR Ca(2+)-uptake have been identified in human heart failure and in animal models of cardiac hypertrophy and failure. These alterations have been associated with a reduction in SERCA2a activity and in steady-state SERCA2a protein and mRNA levels. As a first step in the analysis of the mechanisms responsible for this reduction, we have studied a possible down-regulation of the SERCA2 gene transcription during left ventricular hypertrophy (LVH) induced by constriction of the ascending aorta in the rat. Quantifications of the mRNA levels demonstrated no alteration, compared to sham-operated rats, at 5 d after imposition of the pressure overload, whereas a significant decrease was observed at 11 d. Transcription in-vitro experiments (cardiac nuclear run-on assays) performed in isolated cardiomyocytes nuclei showed no changes at 5 d and a 37% reduction of the SERCA2 gene transcription at 11 d. These results strongly suggest that SERCA2 gene expression down-regulation during cardiac hypertrophy occurs, at least in part, at the level of the transcription.
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PMID:The sarco(endo)plasmic reticulum Ca(2+)-ATPase gene is regulated at the transcriptional level during compensated left ventricular hypertrophy in the rat. 958 74

In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.
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PMID:Effect of inotropic interventions on the force-frequency relation in the human heart. 983 34

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