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)

Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca2+-ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 alpha/beta mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for alpha-MHC, and increased proportion of beta-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of alpha- and beta-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy.
 ...
PMID:Reversal of chronic molecular and cellular abnormalities due to heart failure by passive mechanical ventricular containment. 1464 32

Nkx2.5 is a conserved homeodomain (HD) containing a transcription factor essential for early cardiac development. We generated several mutations modeling some patients with congenital heart disease. Transgenic mice (tg) expressing the wildtype Nkx2.5 under beta-myosin heavy chain (MHC) promoter died during the embryonic stage. However, tg mice expressing this mutation under beta-MHC promoter (beta-MHC-TG(I183P)), the wildtype Nkx2.5 (alpha-MHC-TG(wild)), and a putative transcriptionally active mutant (carboxyl-terminus deletion, alpha-MHC-TG(DeltaC)) under alpha-MHC promoter showed postnatal lethal heart failure. Given the profound atrioventricular conduction abnormalities we recently demonstrated in beta-MHC-TG(I183P) mice, the aim of this study was to determine whether alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mutant mice display similar cardiac electrophysiological phenotypes. Surface ECG recordings and in vivo electrophysiology studies were performed in alpha-MHC-TG(wild) mice and controls at 6 weeks of age, and in alpha-MHC-TG(DeltaC) mice and controls at 10 weeks of age. Ambulatory ECG recordings in alpha-MHC-TG(wild) and controls were obtained using an implantable radiofrequency telemetry system. PR prolongation and atrioventricular nodal dysfunction were detected in alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mice. Bradycardia and prolonged PR interval were seen in ambulatory ECG of alpha-MHC-TG(wild) mice compared to controls. Several alpha-MHC-TG(wild) mice died of bradycardia. Fetal and neonatal mutant Nkx2.5 expression causes severe cardiac conduction failure. Postnatal overexpression of nonmutant (wild) Nkx2.5 also causes conduction abnormalities, although the onset is after the neonatal stage. Bradycardia and AV conduction failure may contribute to the lethal heart failure and early mortality.
 ...
PMID:Cardiac electrophysiological phenotypes in postnatal expression of Nkx2.5 transgenic mice. 1459 38

Cardiac expression of a transgene is a common approach for determining the role of gene products in the processes underlying cardiomyopathy and heart failure (HF). We have generated transgenic mice that express the 'harmless' yeast transcription factor Gal4 in the heart under control of the alpha-myosin heavy chain promoter and found that expression of this gene causes cardiomyopathy and HF, the severity of which correlated with the number of copies of the transgene integrated into the genome and with the expression level. A line with a single copy of the transgene targeted to the hprt locus correctly expressed the transgene but did not develop cardiomyopathy. Our results indicate that expression of a transgene in the heart may non-specifically cause HF in a dose-dependent manner.
 ...
PMID:Cardiac expression of Gal4 causes cardiomyopathy in a dose-dependent manner. 1460 31

Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from alpha-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Galphaq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional alpha-MHC transgenic phenotypes.
 ...
PMID:Physiological growth synergizes with pathological genes in experimental cardiomyopathy. 1553 35

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.
 ...
PMID:Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. 1561 39

Progressive left ventricular (LV) dilation is a characteristic feature of heart failure and is invariably associated with poor long-term prognosis. This review discusses observations made in dogs with chronic heart failure using a passive mechanical containment device, the Acorn Cardiac Support Device (CSD), which is designed to prevent progressive LV enlargement. Studies have shown that, in addition to preventing LV dilation, long-term therapy with the CSD also improved LV ejection fraction, tended to normalize LV shape, reduced LV wall stress, and reduced or eliminated functional mitral regurgitation. At the cellular level, the CSD attenuates cardiomyocyte hypertrophy, reduced oxygen diffusion distance and downregulated stretch response proteins. The CSD also improved calcium cycling within the sarcoplasmic reticulum and upregulated mRNA gene expression for alpha-myosin heavy chain. These findings, when viewed in concert, provide an explanation for mechanisms that may be responsible for the improvement in LV function seen in dogs with heart after long-term CSD therapy.
 ...
PMID:Effects of cardiac support device on reverse remodeling: molecular, biochemical, and structural mechanisms. 1580 52

Serum response factor (SRF) homozygous-null embryos from our backcross of SRF(LacZ/)(+) "knock-in" mice failed to gastrulate and form mesoderm, similar to the findings of an earlier study (Arsenian, S., Weinhold, B., Oelgeschlager, M., Ruther, U., and Nordheim, A. (1998) EMBO J. 17, 6289-6299). Our use of embryonic stem cells provided a model system that could be used to investigate the specification of multiple embryonic lineages, including cardiac myocytes. We observed the absence of myogenic alpha-actins, SM22alpha, and myocardin expression and the failure to form beating cardiac myocytes in aggregated SRF null embryonic stem cells, whereas the appearance of transcription factors Nkx2-5 and GATA4 were unaffected. To study the role of SRF during heart organogenesis, we then performed cardiac-specific ablation of SRF by crossing the transgenic alpha-myosin heavy chain Cre recombinase line with SRF LoxP-engineered mice. Cardiac-specific ablation of SRF resulted in embryonic lethality due to cardiac insufficiency during chamber maturation. Conditional ablation of SRF also reduced cell survival concomitant with increased apoptosis and reduced cellularity. Significant reductions in SRF (> or =95%), atrial naturetic factor (> or =80%), and cardiac (> or =60%), skeletal (> or =90%), and smooth muscle (> or =75%) alpha-actin transcripts were also observed in the cardiac-conditional knock-out heart. This was consistent with the idea that SRF directs de novo cardiac and smooth muscle gene activities. Finally, quantitation of the knock-in LacZ reporter gene transcripts in the hearts of cardiac-conditional knock-out embryos revealed an approximately 30% reduction in gene activity, indicating SRF gene autoregulation during cardiogenesis.
 ...
PMID:Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets. 1592 41

Serum response factor (SRF) is a transcription factor required for the regulation of genes important for cardiac structure and function. Notably, the "fetal gene expression profile" that is characteristic of cardiac hypertrophy consists of genes known to be regulated by SRF. Transgenic animal studies suggest that cardiac-specific overexpression of SRF induces this pattern of hypertrophic genes and subsequently causes the progression of pathologic adaptations. Furthermore, studies examining cardiac tissues from patients with severe heart failure indicate significant alterations in SRF expression that correspond with alterations in expression of SRF-dependent genes. Based on these observations, it has been postulated that SRF may be critical for stimulating pathologic gene expression at the onset of hypertrophic adaptation. To address the role of SRF in cardiac hypertrophy we investigated whether SRF is necessary and sufficient for the expression of genes associated with the hypertrophic response. We used isolated cardiomyocytes from both neonatal rats, and transgenic mice containing floxed SRF alleles, to examine cardiac gene expression in response to overexpression and absence of SRF. Using this approach, we demonstrate that SRF is required for the induction of atrial naturetic factor (ANF), c-fos, NCX1, BNP, alpha-actins, alpha-myosin heavy chain, and beta-myosin heavy chain genes. However, overexpression of exogenous SRF in isolated cardiomyocytes is only sufficient to induce NCX1 and alpha-myosin heavy chain. These results indicate that SRF is critical for the regulation and induction of genes associated with the progression of pathologic cardiac hypertrophy, however, the pattern of genes induced by overexpression of SRF in isolated cardiomyocytes is different from those genes expressed in hypertrophic transgenic hearts. This suggests that SRF-dependent gene expression is modulated in a complex manner by in vivo physiologic systems prior to and during heart failure as the organism adapts to cardiac stress.
 ...
PMID:SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy. 1595 Sep 86

Changes in myosin heavy chain (MHC) isoform expression and protein composition occur during cardiac disease and it has been suggested that even a minor shift in MHC composition may exert a considerable effect on myocardial energetics and performance. Here an overview is provided of the cellular basis of the energy utilisation in cardiac tissue and novel data are presented concerning the economy of myocardial contraction in diseased atrial and ventricular human myocardium. ATP utilisation and force development were measured at various Ca(2+) concentrations during isometric contraction in chemically skinned atrial trabeculae from patients in sinus rhythm (SR) or with chronic atrial fibrillation (AF) and in ventricular muscle strips from non-failing donor or end-stage failing hearts. Contractile protein composition was analysed by one-dimensional gel electrophoresis. Atrial fibrillation was accompanied by a significant shift from the fast alpha-MHC isoform to the slow beta-MHC isoform, whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform. Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure.
 ...
PMID:Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium. 1608 76

Progressive left ventricular (LV) dilation is a characteristic feature of heart failure and is associated with poor long-term prognosis. One of the characteristic changes that occur in the failing heart is a change in gene expression wherein fetal genes that were turned off shortly after birth are re-activated in heart failure and may play a key role in the progressive worsening of the heart failure state. This review discusses reversal of maladaptive gene expression in dogs with chronic heart failure treated long-term with the Acorn Cardiac Support Device (CSD); a passive mechanical device designed to prevent progressive LV enlargement and to restore normal LV chamber geometry. Studies in our laboratories have shown that, in addition to preventing LV dilation and improving LV ejection fraction, long-term therapy with the CSD reverses the maladaptive gene program observed in LV myocardium of dogs with heart failure. Therapy with the CSD was associated with up-regulated mRNA expression for alpha-myosin heavy chain and down-regulated mRNA expression of A- and B- type natriuretic peptides, cytokines and favorably modulated cytoskeletal proteins. These findings provide an explanation for mechanisms that may be partly responsible for the improvement in LV systolic and diastolic function seen in dogs with heart failure after long-term CSD therapy.
 ...
PMID:Reversal of maladaptive gene program in left ventricular myocardium of dogs with heart failure following long-term therapy with the Acorn Cardiac Support Device. 1625 23


<< Previous 1 2 3 4 5 6 7 8 Next >>