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)

We employed Cre/loxP technology to generate mPDK1(-/-) mice, which lack PDK1 in cardiac muscle. Insulin did not activate PKB and S6K, nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate, in the hearts of mPDK1(-/-) mice, consistent with PDK1 mediating these processes. All mPDK1(-/-) mice died suddenly between 5 and 11 weeks of age. The mPDK1(-/-) animals had thinner ventricular walls, enlarged atria and right ventricles. Moreover, mPDK1(-/-) muscle mass was markedly reduced due to a reduction in cardiomyocyte volume rather than cardiomyocyte cell number, and markers of heart failure were elevated. These results suggested mPDK1(-/-) mice died of heart failure, a conclusion supported by echocardiographic analysis. By employing a single-cell assay we found that cardiomyocytes from mPDK1(-/-) mice are markedly more sensitive to hypoxia. These results establish that the PDK1 signalling network plays an important role in regulating cardiac viability and preventing heart failure. They also suggest that a deficiency of the PDK1 pathway might contribute to development of cardiac disease in humans.
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PMID:Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. 1297 Jan 79

Altered cellular adhesion and apoptotic signaling in cardiac remodeling requires coordinated regulation of multiple constituent proteins that comprise cytoskeletal focal adhesions. One such protein activated by cardiac remodeling is related adhesion focal tyrosine kinase (RAFTK, also known as pyk2). Adenoviral-mediated expression of RAFTK in neonatal rat cardiomyocytes involves concurrent increases in phosphorylation of Src, c-Jun N-terminal kinase, and p38 leading to characteristic apoptotic changes including cleavage of poly(ADP-ribose) polymerase, caspase-3 activation, and increased DNA laddering. DNA laddering was decreased by mutation of the Tyr(402) Src-binding site in RAFTK, suggesting a central role for Src activity in apoptotic cell death that was confirmed by adenoviral-mediated Src expression. Multiple apoptotic signaling cascades are recruited by RAFTK as demonstrated by prevention of apoptosis using caspase-3 inhibitor IV (caspase-3 specific inhibitor), PP2 (Src-specific kinase inhibitor), or Csk (cellular negative regulator for Src), as well as dominant negative constructs for p38beta or MKP-1. These RAFTK-mediated phenotypic characteristics are prevented by concurrent expression of wild-type or a phosphorylation-deficient paxillin mutated at Tyr(31) and Tyr(118). Wild-type or mutant paxillin protein accumulation in the cytoplasm has no overt effect upon cell structure, but paxillin accumulation prevents losses of myofibril organization as well as focal adhesion kinase, vinculin, and paxillin protein levels mediated by RAFTK. Apoptotic signaling cascade inhibition by paxillin indicates interruption of signaling proximal to but downstream of RAFTK activity. Chronic RAFTK activation in cardiac remodeling may represent a maladaptive reactive response that can be modulated by paxillin, opening up novel possibilities for inhibition of cardiomyocyte apoptosis and structural degeneration in heart failure.
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PMID:Cardiomyocyte apoptosis triggered by RAFTK/pyk2 via Src kinase is antagonized by paxillin. 1532 13

Cardiac myocyte loss, regardless of insult, can trigger compensatory myocardial remodeling leading to heart failure. Identifying mediators of cardiac myocyte survival may advance clinical efforts toward myocardial preservation. Angiopoietin-1 limits ischemia-induced cardiac injury. This benefit is ascribed to angiogenesis because the receptor, tie2, is largely endothelial-specific. We propose that direct, non-tie2 interactions of angiopoietin-1 on cardiac myocytes contribute to this cardioprotection. We found that mouse C2C12 skeletal myocytes lack tie2, yet dose-dependently adhered to angiopoietin-1 and angiopoietin-2 similarly to laminin, fibronectin, vitronectin, and more than to collagen-I, -III, and -IV. Adhesion was divalent cation-mediated (Mn2+, Ca2+, not Mg2+), blocked with EDTA/EGTA, RGD-based peptides, and select integrin subunit antibodies. Similar findings were obtained with human skeletal myocytes (HSMs) and freshly isolated rat neonatal cardiac myocytes (NCMs). Furthermore, angiopoietin-1 conferred significant survival advantage exceeding that of most cell matrices, which was not fully explained by differences in cell adhesion. Angiopoietin-1 promoted survival of serum-starved C2C12, HSM, and NCM (MTT, trypan blue) and prevented taxol-induced apoptosis (caspase-3). Immobilized and soluble angiopoietin-1 phosphorylated Akt(S473) and MAPK(p42/44), (not FAK(Y397)) in C2C12 more than in endothelial cells and more than did angiopoietin-2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM Akt(S473) and MAPK(p42/44) survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vascular effects alone. Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. 1569 86

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.
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PMID:Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. 1620 18

Biventricular dilation and severe cardiac dysfunction are observed during septic shock. However, when endotoxemia and vasoconstrictor-masked hypovolemia work in concert in the pathogenesis of shock, the clinical scenario is more adverse compared to one of the insults acting alone. Matrix metalloproteinases (MMPs) are involved in chronic and acute heart failure by degrading the mechanical scaffold of the heart and several intracellular proteins. Therefore, the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in hearts of early multiple organ failure induced by norfenefrine-masked hypovolemia and endotoxemia were investigated in an ovine model. Experimental groups included (1) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) (n=6), (2) norfenefrine-masked hypovolemia without endotoxemia (NMH) (n=6), (3) recurrent endotoxemia during normovolemia (ENDO) (n=6), and (4) healthy untreated controls (CON) (n=3). Apoptosis was determined by TUNEL-staining. Gel zymography revealed significantly increased MMP-2 activity in NMH+ENDO compared to ENDO and controls. MMP-9 activity was significantly elevated in all experimental groups. MMP-2 was significantly increased at the protein level, while MMP-9 was unaltered. MT1-MMP was not significantly changed in any group. Increased MMP activities were associated with cardiac deterioration. MMP-2/-9 activity and phosphorylated Paxillin (p-Paxillin) expression correlated positively with cardiomyocyte apoptosis. This study underscores the pivotal roles of MMP in acute cardiac dysfunction during early multiple organ failure in combined vasoconstrictor-masked hypovolemic and endotoxemia shock.
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PMID:Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model. 1630 6

In chronic heart failure (CHF) cardiotrophin-1 (CT-1) and monocyte chemoattractant protein-1 (MCP-1) plasma concentrations are elevated. CT-1 is a cytokine of the interleukin-6 (IL-6) superfamily. Most members of the IL-6 family are able to activate human umbilical vein endothelial cells (HUVEC) but so far there are no data which demonstrate that CT-1 can activate HUVEC. Because MCP-1-as a marker of endothelial activation-is elevated in CHF we examined whether CT-1 will induce MCP-1 production in HUVEC. MCP-1 mRNA levels were determined by real time PCR, RT-PCR and northern blot analysis and MCP-1 protein concentrations in the supernatant by ELISA. Signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (pSTAT3) were investigated by western blot analysis. Incubation of HUVEC with different CT-1 concentrations for various time periods induced time and concentration dependent MCP-1 mRNA. Maximal MCP-1 mRNA was reached after 6h. After 24h CT-1 caused a significant induction of MCP-1 protein in the supernatant compared to control. CT-1 induced concentration dependent phosphorylation of STAT3 without any change in total-STAT3 concentration. Piceatannol-a specific blocker of STAT3 phosphorylation-inhibited CT-1 induced MCP-1 induction completely. AG490-a blocker of the JAK2 pathway-was also able to inhibit CT-1 induced MCP-1 upregulation, indicating that the JAK2 pathway is also necessary for MCP-1 induction. Parthenolide-a blocker of NFkappaB-inhibited CT-1 induced MCP-1 expression, completely. Our data show that CT-1 induces in a concentration and time dependent manner MCP-1 mRNA and protein in HUVEC. STAT3 phosphorylation, the activation of JAK2 and NF-kappaB are involved in this pathway. In CHF, CT-1 may be able to induce MCP-1 which might be responsible for progression of heart failure either by recruiting inflammatory cells within the myocardium or by a direct modulation of myocyte function.
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PMID:Cardiotrophin-1 induces monocyte chemoattractant protein-1 synthesis in human umbilical vein endothelial cells. 1642 85

The mechanical stress imposed by hemodynamic overload on heart walls is a primary event in triggering the cardiac hypertrophic response. Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. In fact, integrins, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy program. In this review, we will discuss the role of the muscle-specific integrin isoform beta1D and of associated proteins such as FAK, melusin, vinculin, zyxin, VASP, and migfilin that are the most upstream elements ("initiators") activated by mechanical strain. These molecules trigger a coordinated downstream signaling cascade involving proteins such as AKT, RAS, and MAPKs that execute the biochemical program leading to cardiomyocyte hypertrophy. Better understanding of the functional role of the initiator elements is of key importance to developing novel strategies to control cardiac hypertrophy and prevent heart failure.
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PMID:Integrin signalling: the tug-of-war in heart hypertrophy. 1646 4

The purpose of the study was to determine the potential beneficial effect of six weeks oral L-arginine supplementation (LAS) on endurance exercise, an important determinant of daily-life activity in patients with chronic stable heart failure (CHF). After an initial incremental maximal exercise test, CHF patients performed an identical thirty-minute interval endurance exercise test before and after six weeks with (L-arginine group; ARG) or without LAS (control group; CTL). Hemodynamic, respiratory, and metabolic parameters were determined at rest, during exercise, and during recovery. Mean heart rate decreased throughout exercise and recovery after LAS (- 8.2 +/- 1.4 b x min(-1); p = 0.003 and - 6.7 +/- 1.6 b x min(-1); p < 0.001, respectively), systemic blood pressure and respiratory parameters remaining unchanged. Resting L-argininaemia increased from 102 +/- 11 to 181 +/- 37 micromol x l(-1) (p < 0.004) and exercise-induced peak increase in plasma lactate was blunted after LAS (4.13 +/- 0.75 vs. 3.13 +/- 0.39 mmol x l(-1); p = 0.02). No significant change was observed in the control group. In heart failure patients, six weeks oral LAS enhances endurance exercise tolerance, reducing both heart rate and circulating lactates. This suggests that chronic LAS might be useful as a therapeutic adjuvant in order to improve the patient's physical fitness.
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PMID:Chronic L-arginine supplementation enhances endurance exercise tolerance in heart failure patients. 1680 53

A requirement for integrin-mediated adhesion in cardiac physiology is revealed through targeted deletion of integrin-associated genes in the murine heart. Here we show that targeted ablation of the integrin-linked kinase (ILK) expression results in spontaneous cardiomyopathy and heart failure by 6 wk of age. Deletion of ILK results in disaggregation of cardiomyocytes, associated with disruption of adhesion signaling through the beta1-integrin/FAK (focal adhesion kinase) complex. Importantly, the loss of ILK is accompanied by a reduction in cardiac Akt phosphorylation, which normally provides a protective response against stress. Together, these results suggest that ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure.
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PMID:Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. 1695 Dec 52

Integrins play a pivotal role in cardiomyocyte survival and function, with integrin loss leading to myocyte apoptosis and heart failure. The aim of this study was to characterize whether regulation of integrins may contribute to cardiac remodeling in human ischemic cardiomyopathy (ICM). Myocardial tissues of the left ventricle were obtained from patients with ICM (n = 8) undergoing cardiac transplantation and from unused donor hearts (NF, n = 8). In addition, tissue samples from patients with dilated cardiomyopathy (DCM, n = 5) were analyzed. Expression of integrins beta(1)D and beta(3), the effector proteins focal adhesion kinase (FAK) and melusin, and FAK phosphorylation were examined by Western blotting, real-time-PCR and immunofluorescence analysis, respectively. Beta(1)D-integrin protein was decreased in ICM vs. NF by 36%. Beta(1)D-integrin mRNA levels and beta(1)D-integrin shedding were unchanged. Corresponding to beta(1)D-integrin regulation, FAK and phosphorylated FAK were decreased in ICM vs. NF by 54% and 49%, respectively. beta(3)-integrin and melusin were not altered in ICM. As a mediator of integrin effects, AKT kinase activity was examined. In parallel to beta(1)D-integrin and FAK, AKT activity was decreased in ICM by 44%. In contrast, none of the proteins were significantly altered in DCM compared to NF. Integrins and integrin signaling are regulated differentially in ICM and DCM with a decrease of beta(1)D-integrin and FAK in ICM. The loss of the beta(1)Dintegrin-FAK-complex in ICM was paralleled by a reduced AKT activity supporting in vitro data which demonstrate the pivotal role of intact integrin function in anti-apoptotic signaling and cell survival.
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PMID:Loss of beta1D-integrin function in human ischemic cardiomyopathy. 1718 62


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