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)

Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been shown to be elevated in the serum of patients with ischemic heart disease and valvular heart disease, and induces cardiomyocyte hypertrophy in vitro. We investigated expression of CT-1 in post-MI rat heart and the effect of CT-1 on cultured primary adult rat cardiac fibroblasts. Elevated CT-1 expression was observed in the infarct zone at 24 h and continued through 2, 4 and 8 weeks post-MI, compared to sham-operated animals. CT-1 induced rapid phosphorylation of Jak, Jak2, STAT1, STAT3, p42/44 MAPK and Akt in cultured adult cardiac fibroblasts. CT-1 induced cardiac fibroblast protein synthesis and proliferation. Protein and DNA synthesis were dependent on activation of Jak/STAT, MEK1/2, PI3K and Src pathways as evidenced by decreased 3H-leucine and 3H-thymidine incorporation after pretreatment with AG490, PD98059, LY294002 and genistein respectively. Furthermore, CT-1 treatment increased procollagen-1-carboxypropeptide (PICP) synthesis, a marker of mature collagen synthesis. CT-1 induced cell migration of rat cardiac fibroblasts. Our results suggest that CT-1, as expressed in post-MI heart, may play an important role in infarct scar formation and ongoing remodeling of the scar. CT-1 was able to initiate each of the processes considered important in the formation of infarct scar including cardiac fibroblast migration as well as fibroblast proliferation and collagen synthesis. Further work is required to determine factors that induce CT-1 expression and interplay with other mediators of cardiac infarct wound healing in the setting of acute cardiac ischemia and chronic post-MI heart failure.
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PMID:Cardiotrophin-1: expression in experimental myocardial infarction and potential role in post-MI wound healing. 1467 4

Obesity is a major risk factor for the development of heart failure. Importantly, it is now appreciated that a change in the number of myocytes is one of multiple structural and functional alterations (remodeling) leading to heart failure. Here we investigate the effect of leptin, the product of the obese (ob) gene, on proliferation of human and murine cardiomyocytes. Leptin caused a time- and dose-dependent significant increase in proliferation of HL-1 cells that was inhibited by preincubation with PD98059 and LY294002, suggesting that leptin mediated proliferation via extracellular signal-regulated kinase-1/2- and phosphatidylinositol-3-kinase-dependent signaling pathways. We confirmed that leptin activates both extracellular signal-regulated kinase-1/2 phosphorylation and association of phosphatidylinositol-3-kinase (regulatory p85 subunit) with phosphotyrosine immunoprecipitates. We also examined bromodeoxyuridine incorporation as a measure of new DNA synthesis and demonstrated a stimulatory effect of leptin in both HL-1 cells and human cardiomyocytes. Bromodeoxyuridine incorporation in HL-1 cells was inhibited by PD98059 and LY294002. Our results establish a mitogenic effect of leptin in cardiomyocytes and provide additional evidence for a potential direct link between leptin and cardiac remodeling in obesity.
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PMID:Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. 1471 11

The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died approximately 7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor beta signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.
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PMID:Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. 1474 26

Osteopontin (OPN), also called cytokine Eta-1, expressed in the myocardium co-incident with heart failure plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Angiotensin II (Ang II) and inflammatory cytokines are increased in the heart following MI. We studied the involvement of mitogen-activated protein kinases (ERK1/2, JNKs, p38 kinase) and reactive oxygen species (ROS) in Ang II- and cytokine-induced OPN gene expression in adult rat cardiac fibroblasts. Ang II alone increased OPN mRNA (3.3 +/- 0.3-folds; P < 0.05; n = 7), while interleukin-1beta (IL-1beta), tumor necrosis factor (TNF-alpha), and interferon-gamma (IFN-gamma) had no effect. A combination of Ang II with IL-1beta or TNF-alpha, not IFN-gamma, increased OPN mRNA more than Ang II alone. Nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), alone or in combination with Ang II had no effect. Diphenylene iodonium (DPI), inhibitor of NAD(P)H oxidase, and tiron, superoxide scavenger, inhibited Ang II- and Ang II+ IL-1beta-stimulated increases in OPN mRNA. Ang II activated ERK1/2 within 5 min of treatment, not JNKs. IL-1beta activated ERK1/2 and JNKs within 15 min of treatment. A combination of Ang II and IL-1beta activated ERK1/2 within 5 min of treatment. None of these stimuli activated p38 kinase. DPI almost completely inhibited Ang II + IL-1beta-stimulated activation of ERK1/2, while partially inhibiting JNKs. PD98059, ERK1/2 pathway inhibitor, and SP600125, JNKs inhibitor, partially inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. A combination of PD98059 and SP600125 almost completely inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. Thus, Ang II alone increases OPN expression, while IL-1beta and TNF-alpha act synergistically with Ang II to increase OPN mRNA possibly via NO independent mechanisms. The synergistic increase in OPN mRNA involves ROS-mediated activation of ERK1/2 and JNKs, not P38 kinase, pathways in cardiac fibroblasts.
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PMID:ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. 1475 45

The use of GH to treat heart failure has received considerable attention in recent years. Although the mechanisms of its beneficial effects are unknown, it has been implicated in the regulation of apoptosis in several cell types, and cardiomyocyte apoptosis is known to occur in heart failure. We therefore decided to investigate whether GH protects cardiomyocytes from apoptosis. Preliminary experiments confirmed the expression of the GH receptor (GHR) gene in primary cultures of neonatal rat cardiomyocytes (PC), the specific binding of GH by HL-1 cardiomyocytes, and the GH-induced activation of GHR and its classical downstream effectors in the latter. That GH prevented the apoptosis of PC cells deprived of serum for 48 h was shown by DNA electrophoresis and by Hoechst staining assays in which GH reduced the percentage of cells undergoing apoptosis. Similarly, the TUNEL-evaluated pro-apoptotic effect of cytosine arabinoside (AraC) on HL-1 cells was almost totally prevented by pre-treatment with GH. Fluorescence-activated cell sorter (FACS) analysis showed apoptosis in 9.7% of HL-1 cells growing in normal medium, 21.1% of those treated with AraC and 13.9% of those treated with AraC+GH, and that GH increased the percentage of AraC-treated cells in the S/G(2)/M phase from 36.9% to 52.8%. GH did not modify IGF-I mRNA levels or IGF-I secretion in HL-1 cells treated with AraC, and the protection afforded by GH against AraC-induced apoptosis in HL-1 cells was not affected by the presence of anti-IGF-I antibodies, but was largely abolished by the calcineurin-inhibiting combination cyclosporin+FK506. GH also reduced AraC-induced phosphorylation of mitogen-activated protein kinase p38 (MAPK p38) in HL-1 cells. In summary, GH protects PC and HL-1 cells from apoptosis. This effect is not mediated by IGF-I and may involve MAPK p38 as well as calcineurin.
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PMID:GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. 1476 85

Beta-adrenergic receptor (beta-AR) blockade is now widely utilized therapeutically for heart failure, but its cellular mechanism of action is not clear. Mice with cardiac-specific overexpressed Gs alpha develop cardiomyopathy with age, which can be prevented by beta-AR blockade, making this model potentially useful for addressing this question. Our hypothesis was that distal mechanisms in beta-AR signaling, i.e. mitogen-activated protein kinases, were a potential mechanism. At 6-9 months, when cardiomyopathy began to develop in Gs alpha mice, there were significant increases in phospho-kinase levels of p38 MAP kinase (p38 MAPK), and p70(S6K) compared to wild type. In contrast, phospho-kinase levels of ERK and Akt were increased at 9-10 months, but phospho-kinase levels of c-Jun N-terminal kinase (JNK) increased only at 15-20 months (when cardiomyopathy was fully manifest). Treatment of 9-10 months old Gs alpha mice with propranolol for 5 weeks reverted the phospho-kinase levels of these kinases known to be involved in the growth and death of cardiac myocytes. Another novel observation of this study was that there were also decreases in total protein levels of p38 MAPK, p70(S6K), JNK, and Akt following beta-AR blockade. Thus, chronically enhanced beta-AR signaling elicits a differential pattern of altered mitogen-activated protein kinases, which was reversed with beta-AR blockade, raising the possibility that the beneficial effects of beta-AR blockade therapy in heart failure may be due in part to the inhibition of these pathways.
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PMID:Propranolol prevents enhanced stress signaling in Gs alpha cardiomyopathy: potential mechanism for beta-blockade in heart failure. 1487 58

Activation of stress-activated mitogen-activated protein kinases (SAPKs), mainly c-Jun N-terminal kinase (JNK) and p38, have long been associated with different forms of cardiac pathology across a wide spectrum of species. However, their specific roles in the development of heart failure are still unclear. Previous studies in neonatal myocytes in culture suggest a critical role for both JNK and p38 in hypertrophy and apoptosis. A far more complex picture has been provided by recent observations from both cellular and transgenic models that have not only challenged their role in hypertrophy and cell death but have also pointed out novel functions of SAPKs in different aspects of cardiac pathology, including contractile function, extracellular matrix remodeling, intercellular communication, and metabolic regulation.
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PMID:Stress-activated MAP kinases in cardiac remodeling and heart failure; new insights from transgenic studies. 1503 Jul 89

Accumulating data support the idea that apoptosis in cardiac myocytes, in part, contributes to the development of heart failure. Since a number of neurohormonal factors are activated in this state, these factors may be involved in the positive and negative regulation of apoptosis in cardiac myocytes. Norepinephrine is one such factor and induces apoptosis in cardiac myocytes via a beta-adrenergic receptor pathway. beta-adrenergic agonist-induced apoptosis in cardiac myocytes is dependent on the activation of the cAMP/protein kinase A pathway. Interestingly, the activation of this pathway protects PC12 cells from apoptosis, suggesting that cAMP/protein kinase A regulates apoptosis in a cell type-specific manner. Another neurohormonal factor activated in heart failure is endothelin-1, which acts as a potent survival factor against myocardial cell apoptosis. Intracellular signaling pathways for endothelin-1-mediated protection include activation of MEK-1 /ERK1/2 and PI3 kinase. In addition to these protective pathways common among cell types, endothelin- activates the calcium-activated phosphatase calcineurin, which is necessary for the nuclear import of NFAT transcription factors. These factors interact with the cardiac-restricted zinc finger protein GATA-4 and induce transcription and expression of anti-apoptotic molecule bcl-2. Thus, myocardial cell apoptosis is regulated by pathways unique to cardiac myocytes as well as by those common among cell types. It should be further determined whether agents that specifically block myocardial cell apoptosis will attenuate the progression of heart failure.
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PMID:Intracellular signaling pathways for norepinephrine- and endothelin-1-mediated regulation of myocardial cell apoptosis. 1512 20

Fibroblasts are responsible in large part for production, organization, and turnover of the extracellular matrix (ECM), thereby regulating the fibrotic content of the heart. Excessive fibrosis, which has been associated with certain forms of hemodynamic overload such as hypertension, is thought to result in increased ventricular chamber stiffness, and eventual heart failure. As such, the role of mechanical stretch in regulating fibroblast activity is crucial to our understanding of healthy and diseased hearts. However, little is known about the effects of alterations in the composition of the ECM in regulating mechanotransduction in cardiac fibroblasts. In order to address this question, rat cardiac fibroblasts were cultured on silastic membranes coated with different ECM substrates, and cyclically stretched for various durations. Experiments were designed to assess the activation of signaling pathways, as well as changes in collagen production, cellular proliferation, and morphology. Mitogen activated protein kinase (MAP kinase) was most rapidly activated, and collagen I expression was most abundant, in cells stretched on randomly organized collagen, and uncoated charged membranes. Regardless of the nature of the ECM substrate, stretched cells decreased proliferation, however, this effect was most marked in cells stretched on randomly organized collagen. Finally, cells stretched on all ECM substrates increased their surface area, but this was observed most significantly in cells adherent to aligned collagen, randomly organized collagen, and uncoated, charged membranes. Taken together, these results suggest cardiac fibroblasts may differentially interpret a mechanical stimulus, in terms of both signal transduction, and specific long-term events such as gene transcription, based on the composition and organization of the ECM.
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PMID:Influence of the extracellular matrix on the regulation of cardiac fibroblast behavior by mechanical stretch. 1525 65

Lysophosphatidic acid (LPA) is a bioactive phospholipid having growth factor-like activity on fibroblasts and is involved in cardiovascular diseases such as hypertension and heart failure by inducing vascular remodeling, characterized by fibroblast proliferation and migration in adventitia. Among various bioactive factors that LPA works with, adrenomedullin (ADM) is a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We studied rat aortic adventitia to explore the possible paracrine/autocrine interaction between endogenous ADM and LPA. LPA stimulation of the adventitia to secrete ADM and express its mRNA was concentration dependent. ADM inhibited LPA-induced proliferation in adventitial cells and attenuated the activity of mitogen-activated protein kinase (MAPK) stimulated by LPA. In contrast, treatment with specific antagonists of the ADM receptor potentiated the LPA-induced proliferation in adventitial cells. We concluded that LPA stimulates the adventitia to produce and secrete ADM, which in turn regulates the vascular biological effects of LPA.
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PMID:Effects of adrenomedullin on cell proliferation in rat adventitia induced by lysophosphatidic acid. 1525 73


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