Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myocardial molecular and cellular responses to hemodynamic and other hypertrophic stimuli have been characterized extensively, but less is known of the alterations in gene expression during the evolution of heart failure following myocardial infarction, and specifically those affecting the cardiac myocytes. Therefore, the present study was undertaken to test the hypothesis that post-infarction heart failure and remodeling in the rat is associated with a distinct myocyte molecular phenotype. To address this question, hemodynamic measurements were performed in vivo; and myocytes isolated from the non-infarcted myocardium 1 day, 1 week, and 6 weeks post-coronary artery ligation in post-infarct rats and sham controls. Myocyte size, mRNA levels for immediate early genes, contractile proteins, and sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban were assayed by Northern analyses, and SERCA and phospholamban proteins were examined by Western blotting. Hemodynamic evidence of heart failure was present at all post-infarct time points. Myocyte size was increased significantly at 6 weeks. c-myc expression was increased at 1 day and 1 week in the infarcted rats, but returned to baseline by 6 weeks. Atrial natriuretic peptide and VEGF mRNAs were elevated at 1 and 6 weeks. Both beta-myosin heavy chain and skeletal alpha-actin expression were increased at all post-MI time points. In contrast, neither changes in the expression of the calcium-handling proteins (SERCA and phospholamban) were not observed, nor was there a change in TGFbeta1 or TGFbeta3. These results demonstrate that in rats with post-MI heart failure, there was an immediate induction of the fetal/embryonic transcriptional gene program which preceded myocyte hypertrophy and appeared to persist longer than in pressure-overload models. In further contrast to pressure-overload, expression of sarcoplasmic reticulum Ca2+-ATPase and phospholamban, was not altered despite a comparable degree of cellular hypertrophy and more severe hemodynamic decompensation. These findings suggest that there may be important differences in the regulatory mechanisms underlying these two forms of myocardial hypertrophy and heart failure.
 ...
PMID:Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. 973 47

The binding of ligands to gp130 activates the JAK/STAT signal transduction pathway, where STAT3 plays a central role in transmitting signals from the membrane to the nucleus. STAT3 is essential for gp130-mediated cardiac myocyte hypertrophy. Cardiac-specific disruption of gp130 was shown to present heart failure in response to mechanical stress accompanied by an increase in apoptosis. Thus, the inactivation of STAT3 resulting from the loss of gp130 may be a key event in the transition from cardiac hypertrophy to heart failure. Proper vascular growth is essential for normal cardiac development and remodeling process. Recently, bcl-xL and VEGF have identified as target genes of STAT and together can promote cardiac myocyte survival by prevention of apoptosis and restoration of energy deprivation. In this review, STAT3 is highlighted as a regulator of angiogenic factors, and activation of STAT-mediated signaling in the cardiac myocyte is proposed as a novel therapeutic strategy for the prevention of heart failure.
 ...
PMID:A novel role for STAT3 in cardiac remodeling. 1134 70

We recently demonstrated that mice deficient in endothelial nitric oxide (NO) synthase (eNOS) have congenital septal defects and postnatal heart failure. However, the mechanisms by which eNOS affects heart development are not clear. We hypothesized that deficiency in eNOS impairs myocardial angiogenesis. Myocardial capillary densities were measured morphometrically in neonatal mouse hearts. In vitro tube formation on Matrigel was investigated in cardiac endothelial cells. In vivo myocardial angiogenesis was performed by implanting Matrigel in the left ventricular myocardium. Myocardial capillary densities and VEGF mRNA expression were decreased in neonatal eNOS(-/-) compared with neonatal wild-type mice (P < 0.01). Furthermore, in vitro tube formation from cardiac endothelial cells and in vivo myocardial angiogenesis were attenuated in eNOS(-/-) compared with wild-type mice (P < 0.01). In vitro tube formation was inhibited by N(G)-nitro-l-arginine methyl ester in wild-type mice and restored by a NO donor, diethylenetriamine-NO, in eNOS(-/-) mice (P < 0.05). In conclusion, deficiency in eNOS decreases VEGF expression and impairs myocardial angiogenesis and capillary development. Decreased myocardial angiogenesis may contribute to cardiac abnormalities during heart development in eNOS(-/-) mice.
 ...
PMID:Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis. 1238 4

The binding of ligands to gp130 activates the JAK/STAT pathway, where STAT3 plays a central role in transmitting signals from the membrane to the nucleus. Cardiac-specific disruption of gp130 was shown to present heart failure in response to mechanical stress accompanied by an increase in apoptosis. Thus, the inactivation of STAT3 resulting from the loss of gp130 may be a key event in the transition from cardiac hypertrophy to heart failure. Vascular formation mediated by VEGF is known to be an essential in the maintenance of cardiac function. In this review, STAT3 is highlighted as a regulator of antiogenic factors, and together with bclxL and MnSOD, promotes cardiac myocyte survival by prevention of apoptosis and restoration of energy deprivation. Cytoprotective signal through gp130 would provide new insight into the pathophysiologic significance of cytokines in the process of cardiac remodeling.
 ...
PMID:Gp130-mediated pathway and left ventricular remodeling. 1255 48

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.
 ...
PMID:Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks. 1487 6

Dietary copper (Cu) restriction leads to cardiac hypertrophy and failure in mice, and Cu repletion (CuR) reverses the hypertrophy and prevents the transition to heart failure. The present study was undertaken to determine changes in myocardial gene expression involved in Cu deficient (CuD) cardiomyopathy and its reversal by CuR. Analysis was performed on three groups of mice: 4-week-old CuD mice that exhibited signs of cardiac failure, their age-matched copper-adequate (CuA) controls, and the CuD mice that were re-fed adequate Cu for 2 weeks. Total RNA was isolated from hearts and subjected to cDNA micro-array and real-time reverse transcription-polymerase chain reaction analysis. Dietary CuD caused a decrease in cardiac mRNA of beta-MHC, L-type Ca(2+) channel, K-dependent NCX, MMP-2, -8, and -13, NF-kappaB, and VEGF. The mRNA levels of ET-1, TGF-beta, TNF-alpha, and procollagen-I-alpha1 and III-alpha1 were increased in the CuD cardiac tissue. Copper repletion resulted in cardiac mRNA levels of most of the genes examined returning to control levels, although the K-dependent NCX and MMP-2 values did not reach those of the CuA control. In addition, CuR caused an increase in beta-MHC, L-type Ca(2+)channel, MMP-13 to levels surpassing those of CuA control, and a decrease in ET-1, and TNF-alpha mRNA levels. In summary, changes in gene expression of elements involved in contractility, Ca(2+) cycling, and inflammation and fibrosis may account for the altered cardiac function found in CuD mice. The return to normal cardiac function by CuR may be a result of the favorable regression in gene expression of these critical components in myocardial tissue.
 ...
PMID:Dietary copper restriction-induced changes in myocardial gene expression and the effect of copper repletion. 1522 55

It is well established that cardiac failure increases cardiac B-type natriuretic peptide (BNP) expression due to myocardial stretching. However, patients with ischemic heart disease also display increased plasma BNP and proBNP concentrations despite preserved cardiac function. In this study, we examined whether acute myocardial hypoxia increases cardiac BNP expression. Surgical reduction of the blood flow to an area of the anterior ventricular wall in pigs reduced the myocardial oxygen tension from 46 +/- 4 to 13 +/- 5 mmHg. The tissue contents of VEGF and BNP mRNA increased 1.8-fold and 3.5-fold, respectively (n=10, P<0.005) in hypoxic compared with normoxic ventricular myocardium after 2.2 +/- 0.2 h; the magnitude of the increase in BNP mRNA expression was positively correlated with that of VEGF in hypoxic myocardium (r=0.66, P<0.05). In support of a hypoxia-induced increase of BNP gene transcription, the content of a premature BNP mRNA was increased in hypoxic myocardium (4.8-fold, P<0.005) and in freshly harvested ventricular myocytes when kept in culture flasks and oxygen-deprived for 3 h (2.2-fold, P=0.002). ProBNP peptide accumulated in the medium of freshly harvested ventricular myocyte cultures but was undetectable in ventricular myocardium, indicating rapid release of the newly synthesized proBNP peptide. Accordingly, the plasma proBNP concentration increased after 2 h of myocardial hypoxia (P=0.028). Cumulatively, the data suggest that acute hypoxia stimulates cardiac BNP expression.
 ...
PMID:Acute myocardial hypoxia increases BNP gene expression. 1557 92

Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-alpha (HIF-1alpha) are important regulators of endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1 analog treatment in patients with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have investigated the effects of the PGE1 analog alprostadil on eNOS, VEGF, and HIF-1alpha expression in human umbilical vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition, we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF, treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA expression in HUVEC and decreases HIF-1alpha. Hypoxia potently increased eNOS, VEGF, and HIF-1alpha synthesis. The alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126. Consistently, the expression of eNOS and VEGF was increased, and HIF-1alpha was reduced in failing hearts treated with alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with HF where endothelial dysfunction is involved in the disease process.
 ...
PMID:PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells. 1595 50

Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.
 ...
PMID:Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. 1607 47

Angiogenesis and improved left ventricular function as a consequence of long-term bradycardia were first demonstrated in normal hearts, either electrically paced (rabbits, pigs) or treated with a selective sinus blocking drug alinidine (rats). Here we review the evidence that chronic heart rate reduction can have similar effects in the heart with compromised vascular supply, due to either hypertensive or haemodynamic overload hypertrophy (rats, rabbits) or ischaemic damage (rats, rabbits, pigs). Bradycardia induced over several weeks increased capillarity in all hypertrophied hearts, and in border and remote left ventricular myocardium of infarcted hearts. In some, but not all cases, coronary blood flow was improved by heart rate reduction, suggesting enlargement of the resistance vasculature in some circumstances. Cardiac or left ventricular function indices, which were depressed by hypertrophy or ischaemic damage, were preserved or even enhanced by chronic heart rate reduction. The expansion of the capillary bed in the vascularly compromised heart induced by bradycardia may be stimulated by mechanical stretch of the endothelium and/or VEGF activated by chamber dilation and myocyte stretch. The increased number of capillaries and more homogeneous distribution of capillary perfusion would support the better pump function, even in the absence of higher coronary flow. The beneficial impact of chronic heart rate reduction on myocardial angiogenesis and function in cardiac hypertrophy and infarction may be major factor in the success of beta-blockers in treatment of human heart failure.
 ...
PMID:Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia. 1630 35


1 2 3 4 5 6 7 8 9 10 Next >>