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)

Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
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PMID:Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. 944 16

Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia. The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hearts were perfused by the Langendorff method and were exposed to ischemia, hypoxia, H(2)O(2), or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms alpha, beta(2), gamma, and zeta, and H(2)O(2) translocated PKC isoforms alpha, beta(2), and zeta. Angiotensin II produced translocation of alpha, beta(2), epsilon, gamma, and zeta isoforms. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (alpha, beta(2), and zeta) and angiotensin II-induced (alpha, beta(2), gamma, and zeta) translocation of PKC isoforms. Inhibition of tyrosine kinase with genistein blocked translocation of PKC isoforms by hypoxia (beta(2) and zeta) and by angiotensin II (beta(2)). By contrast, neither D609 nor genistein blocked H(2)O(2)-induced translocation of any PKC isoform. We conclude that hypoxia-induced activation of PKC isoforms is mediated through pathways involving phospholipase C and tyrosine kinase, but oxidative stress may activate PKC isoforms independently of Galphaq-phospholipase C coupling and tyrosine kinase signaling. Because oxidative stress may directly activate PKC, and PKC activation appears to be involved in human heart failure, selective inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.
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PMID:Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. 1043 69

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.
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PMID:Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. 1082 15

Cardiac hypertrophy is a major predictor of heart failure and of morbidity and mortality in developed countries. Many hormones and growth factors induce cardiac hypertrophy via activation of members of the phospholipase C (PLC) family. The expression pattern of the PLCbeta isozyme subfamily was investigated in neonatal rat cardiomyocytes after stimulation with different hypertrophic stimuli. Under control conditions and after stimulation with norepinephrine, cardiomyocytes expressed similar amounts of PLCbeta3 mRNA. In the presence of fetal calf serum (FCS), additional expression of PLCbeta1 was induced. Growth hormone (GH) and insulin-like growth factor-I (IGF-I) both induced a substantial increase in PLCbeta3 mRNA expression. The response to GH could not be abolished by the IGF-I receptor blocker IGF-I analogue indicating an IGF-I-independent action of GH. The upregulation of PLCbeta3 by IGF-I was abolished by preincubation of cardiomyocytes with the IGF-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor genistein, the extracellular signal-related kinase (ERK) inhibitor PD 98059, the phosphatidylinositol-3- (PI-3) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin. Induction of the immediate early genes c-myc, c-fos, and c-jun by IGF-I was abolished by preincubation with antisense oligos against PLCbeta3. It is concluded that the expression of PLCbeta isozymes in cardiomyocytes is differentially regulated by different hypertrophic stimuli. The upregulation of PLCbeta3 by IGF-I is dependent on the activity of tyrosine kinase, ERK, PI3 kinase, and p70 S6 kinase and PLCbeta3 expression seems to be required for the induction of immediate early genes by IGF-I. The involvement of the PLCbeta subfamily in signal transduction of receptors other than G-protein-coupled receptors is suggested.
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PMID:Differential regulation of phospholipase C-beta isozymes in cardiomyocyte hypertrophy. 1094 30

Ischemic heart disease is more prevalent in men than in women. The remodeling of extracellular matrix, is a structural correlate of heart failure of ischemic origin and proliferation of cardiac fibroblasts is a key factor in this remodeling. We asked if proliferative response of male and female cardiac fibroblasts is differentially susceptible to hypoxia. DNA synthesis, using 3H-thymidine incorporation was compared under hypoxia (2% O2) in cardiac fibroblasts obtained from adult, age-matched male and female rat heart. In female cells DNA synthesis remained unchanged under hypoxia and this resistance was dependent on tyrosine kinase activation, as it was abolished in the presence of genistein, a tyrosine kinase inhibitor. Male cells, on the other hand, were susceptible to hypoxia and their DNA synthesis was reduced significantly (70%, (p < 0.0001). This effect was partially reversed by inhibition of tyrosine kinase. Western analysis showed a higher abundance of tyrosine phosphorylated proteins in male cells compared to female cells as well as differences in molecular weight of basal and hypoxia-induced tyrosine-phosphorylated proteins between male and female cells. The presence of estrogen (17-beta estradiol, 10 nM) altered the response of both cells to hypoxia. In female cells the combined effect of hypoxia and estrogen led to inhibition of DNA synthesis, whereas in male cells estrogen partially reversed the hypoxia-induced inhibition of DNA synthesis (37% (p < 0.01) inhibition in the presence of estrogen vs. 70% (p < 0.0001) inhibition in the absence of estrogen). The effects of estrogen in male and female cells were mediated via estrogen receptors as they were reversed by the pure anti-estrogen, ICI 182,780. Western analysis of cell lysate showed hypoxia-induced increase in the level of estrogen receptor beta in both male and female cells. Gel shift analysis showed hypoxia-induced increase in cytoplasmic ERE (estrogen response element)-binding activity and decrease in nuclear ERE-binding in male cells. In female cells cytoplasmic and nuclear ERE-binding activities remained unchanged under hypoxia. Together, these data demonstrate that while female cells are resistant to hypoxia-induced inhibition in DNA synthesis, male cells are susceptible; intracellular pathways involving tyrosine phosphorylation are involved in the response of both cells; and estrogen, via estrogen-receptor-dependent mechanisms, differentially alters the response of male and female cells to hypoxia.
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PMID:Gender-related differences in proliferative response of cardiac fibroblasts to hypoxia: effects of estrogen. 1120 52

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.
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PMID:Src and Rac mediate endothelin-1 and lysophosphatidic acid stimulation of the human brain natriuretic peptide promoter. 1123 Mar 22

Growth hormone (GH) has been reported to be useful to treat heart failure. To elucidate whether GH has direct beneficial effects on the heart, we examined effects of GH on oxidative stress-induced apoptosis in cardiac myocytes. TUNEL staining and DNA ladder analysis revealed that hydrogen peroxide (H2O2)-induced apoptosis of cardiomyocytes was significantly suppressed by the pretreatment with GH. GH strongly activated extracellular signal-regulated kinases (ERKs) in cardiac myocytes and the cardioprotective effect of GH was abolished by inhibition of ERKs. Overexpression of dominant negative mutant Ras suppressed GH-stimulated ERK activation. Overexpression of Csk that inactivates Src family tyrosine kinases also inhibited ERK activation evoked by GH. A broad-spectrum inhibitor of protein tyrosine kinases (PTKs), genistein, strongly suppressed GH-induced ERK activation and the cardioprotective effect of GH against apoptotic cell death. GH induced tyrosine phosphorylation of EGF receptor and JAK2 in cardiac myocytes, and an EGF receptor inhibitor tyrphostin AG1478 and a JAK2 inhibitor tyrphostin B42 completely inhibited GH-induced ERK activation. Tyrphostin B42 also suppressed the phosphorylation of EGF receptor stimulated by GH. These findings suggest that GH has a direct protective effect on cardiac myocytes against apoptosis and that the effect of GH is attributed at least in part to the activation of ERKs through Ras and PTKs including JAK2, Src, and EGF receptor tyrosine kinase.
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PMID:Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes. 1168 20

Cardiac hypertrophy often leads to heart failure and is associated with abnormal myocardial adrenergic signaling. This enlargement of myocardial mass can involve not only an increase in cardiomyocyte size, but increased proliferation of cardiac fibroblasts. A potential key player in the cardiac hypertrophic response is the ERK family of MAPKs. To gain mechanistic insight into adrenergic regulation of myocardial mitogenic signaling, we examined beta-adrenergic receptor (beta-AR) stimulation of ERK activation and DNA synthesis in cultured adult rat cardiac fibroblasts, including the involvement of tyrosine kinases in this signaling pathway. Addition of the beta-AR agonist isoproterenol (ISO) to serum-starved cells induced DNA synthesis in a dose-dependent manner, and this was inhibited by selective inhibitors of the epidermal growth factor receptor (EGFR). Importantly and in agreement with the involvement of MAPKs and the EGFR in this response in cardiac fibroblasts, the EGFR inhibitor AG1478 attenuated ISO-induced ERK phosphorylation. Moreover, pretreatment with PP2, a selective inhibitor of the Src tyrosine kinase, attenuated both ISO-mediated EGFR phosphorylation and ERK activation. Furthermore, studies in these cardiac fibroblasts showed that phosphatidylinositol 3-kinase contributed to beta-AR-mediated ERK activation, but not to EGFR activation. Finally, studies using selective inhibitors of matrix metalloproteases indicated that they and heparin-bound EGF shedding were involved in beta-AR-induced ERK activation and subsequent DNA synthesis in cardiac fibroblasts. Because these cells primarily express the beta(2)-AR subtype, our findings indicate that beta(2)-AR-mediated EGFR transactivation of intracellular tyrosine kinase signaling pathways is the major signaling pathway responsible for the adrenergic stimulation of mitogenesis of cardiac fibroblasts.
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PMID:Beta-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases. 1204 15

The precise correlation between magnesium and cardiac disease remains to be established. Matrix metalloproteinases (MMPs) are important in cardiac disease such as heart failure. Cardiac fibroblasts are the most abundant cell type in the heart and play an important role in the regulation of collagen degradation by MMPs. To assess the association between magnesium and MMPs, we examined the effects of different extracellular magnesium concentrations (0-3.0 mmol/L) on MMP-2 production in cultured rat cardiac fibroblasts. Using gelatin zymography and western blotting, we found that magnesium reduced MMP-2 production dose-dependently, and this effect was inhibited by the tyrosine kinase inhibitors, genistein or herbimycin A. The results of this study indicated that the beneficial effect of magnesium supplementation on the cardiac disease may be due, at least in part, to the inhibitory effect of magnesium on production of MMPs in cardiac fibroblasts, which appears to be mediated by a protein tyrosine phosphorylation related signal transduction pathway.
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PMID:Effects of magnesium on matrix metalloproteinase-2 production in cultured rat cardiac fibroblasts. 1522 43

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) beta1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic d P/d t, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.
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PMID:Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27. 1537 67


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