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)

Alcoholic heart muscle disease is characterized by structural changes which include chamber dilation, ventricular hypertrophy, and myocyte damage. These effects often lead to contractile dysfunction and ultimately to heart failure if alcohol consumption is not terminated. In rat models for heart failure in which heart failure is induced by pressure or volume overload, there is a shift in the myosin heavy chain (MHC) isoforms, from alpha to beta. As a result of this MHC transition, there is typically a decrease in myosin ATPase activity. We utilized a rat model of chronic alcohol consumption in order to determine if alcohol causes a similar shift in MHC isoforms and changes in myosin ATPase activity. A liquid diet containing 9% ethanol (46% of daily calories; 11.8 g/kg/day) was administered to adult rats for a period of 60 or 90 days. This heavy consumption of ethanol resulted in an average blood ethanol content of 150 mg %. The relative abundance of beta-MHC isoform protein increased from a control level of 9.7% to 35.1% in hearts of ethanol-fed rats, following 90 days of ethanol consumption. In a separate set of experiments, the levels of alpha-MHC and beta-MHC mRNA were demonstrated to increase by 150% and 230%, respectively. Following a 60 day treatment, there was a significant reduction in the actomyosin Mg2+ -ATPase activity in the myofibrillar preparations from hearts of ethanol-fed rats compared to hearts from control-fed rats. In addition, the myosin Ca2+ -ATPase activity was decreased 17% and 30% after 60 and 90 days of ethanol consumption, respectively. The present study demonstrates that chronic ethanol consumption induces an increase in the proportion of the total MHC content composed of the beta-isoform. This isoform transition is accompanied by an accumulation of beta-MHC mRNA, suggesting that the switch is organized pretranslationally. A functional consequence of this transition in MHC phenotype is demonstrated by significant decreases in the myofibrillar and myosin ATPase activities.
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PMID:Heavy long-term ethanol consumption induces an alpha- to beta-myosin heavy chain isoform transition in rat. 1065 Nov 60

To investigate the molecular basis of the decrease in myocardial contractility during heart failure, an animan model of heart failure was set up by means of deoxycorticosterone-acetate impregnated silicone rubber implants in wistar rats. Cardiac contractility in normal and heart failure rats was examined, and gene expression of its myocardial contractile protein, alpha-MHC, was quantitatively analyzed at gene transcription level by using RNA slot blot hybridization. The results showed that the cardiac contractility and the alpha-MHC mRNA levels in heart failure rats were all lower than those in the normal. Statistical analysis showed a positive correlation between the cardiac contractility and the gene expression of alpha-MHC (r = 0.4143, n = 43, P < 0.05). The above results indicate that gene expression level of alpha-MHC is one of the key factors determining cardiac contractility.
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PMID:[Relationship between the expression level of alpha-MHC gene and cardiac contractility during heart failure]. 1068 70

Thyroid hormone deficiency has profound effects on the cardiovascular system, resulting in decreased cardiac contractility, adrenergic responsiveness, and vascular volume and increased peripheral vascular resistance. To determine the importance of direct cardiac effects in the genesis of hypothyroid cardiac dysfunction, the cardiac myocyte was specifically targeted with a mutant thyroid hormone receptor (TR)-beta (Delta337T-TR-beta(1)) driven by the alpha-myosin heavy chain (alpha-MHC) gene promoter. As a control in these experiments, a wild-type (Wt) TR-beta(1) was also targeted to the heart by using the same promoter. Transgenic mice expressing the mutant TR displayed an mRNA expression pattern consistent with cardiac hypothyroidism, even though their peripheral thyroid hormone levels were normal. When these animals were rendered hypothyroid or thyrotoxic, mRNA expression of MHC isoforms remained unchanged in the hearts of the Delta337T transgenic animals, in contrast to Wt controls or transgenic animals expressing Wt TR-beta(1), which exhibited the expected changes in steady-state MHC mRNA levels. Studies in Langendorff heart preparations from mutant TR-beta(1) transgenic animals revealed evidence of heart failure with a significant reduction in +dP/dT, -dP/dT, and force-frequency responses compared with values in Wt controls and transgenic mice overexpressing the Wt TR-beta(1). In contrast, in vivo measures of cardiac performance were similar between Wt and mutant animals, indicating that the diminished performance of the mutant transgenic heart in vitro was compensated for by other mechanisms in vivo. This is the first demonstration indicating that isolated cardiac hypothyroidism causes cardiac dysfunction in the absence of changes in the adrenergic or peripheral vascular system.
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PMID:Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor. 1074 7

The beta(1)-adrenergic receptor (AR) is the dominant subtype in non-failing and failing myocardium. beta(1)-AR signaling, by the endogenous neurotransmitter norepinephrine, is central to the regulation of myocardial contractility. In heart failure, the beta(1)-AR undergoes subtype-selective downregulation which may protect against the increased cardiac adrenergic drive associated with this pathophysiological state. To examine the hypothesis that chronically increased beta(1)-AR mediated signaling has adverse myocardial effects, transgenic mice overexpressing the human beta(1)-AR in a cardiac-selective context were produced, utilizing an alpha-myosin heavy chain (MHC) promoter. In these mice, beta(1)-AR protein abundance was approximately 24-46-fold (1-2 pmol/mg protein) that of wild-type mice. Histopathological examination of young (4 months old) and old (approximately 9 months old) transgenic mouse hearts consistently demonstrated large areas of interstitial replacement fibrosis, marked myocyte hypertrophy and myofibrilar disarray. In addition, increased expression of the pre-apoptotic marker, Bax, was observed coincident with regions of fibrosis accompanied by an increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice exhibited a slight tendency towards a decreased fractional shortening, whereas older beta(1)-AR transgenic mice had a marked reduction in fractional shortening (%FS approximately 30) as determined by echocardiography. Additionally, older beta(1)-AR transgenic mice had an increased left ventricular chamber size. In summary, cardiac-directed overexpression of the human beta(1)-AR in transgenic mice leads to a significant histopathological phenotype with no apparent functional consequence in younger mice and a variable degree of cardiac dysfunction in older animals. This model system may ultimately prove useful for investigating the biological basis of adrenergically-mediated myocardial damage in humans.
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PMID:Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice. 1077 86

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca(2+)) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP(Rx) started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, alpha-myosin heavy chain (MHC) gene expression and protein were decreased, the Ca(2+) transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na(+)/Ca(2+) exchanger mRNA levels increased in comparison to WKY. Active stress development at L(max) and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca(2+) levels. In CAP(Rx) SHR, alpha-MHC gene expression and protein levels were increased, the Ca(2+) transient was not prolonged, Na(+)/Ca(2+) exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of alpha-MHC mRNA in conjunction with an increase in V(1) myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to beta-adrenergic stimulation in CAP(Rx) SHR appears to be coupled to normalization of Na(+)/Ca(2+) exchanger mRNA expression, upregulation of V(1) myosin isozyme levels, and increased speed of contraction.
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PMID:Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. 1085 64

Dietary selenium deficiency represents an etiological factor in "Keshan disease", a distinct form of an endemic cardiomyopathy. The biochemical effects of selenium depletion in the myocardium are, however, not yet known. Therefore, we investigated the changes in the myocardial protein pattern in rats after long-term selenium deficiency. The myocardial proteins were analyzed in samples from five selenium-depleted rats (Se-deficient group) and five rats supplied with adequate amounts of the element (Se-adequate group). Isoelectric focusing (IEF) with carrier ampholytes on large 2-DE gels was used for the separation of proteins in the first dimension and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for the second dimension. The protein patterns were evaluated by means of a computer-assisted gel analysis system. The biochemical identification of the proteins of interest was achieved by matrix-assisted laser desorption/ionization mass spectrometry (MALDI) or immunoblotting. On average, 588 +/- 68 protein spots were found on the gels. No significant difference in spot numbers existed between the groups. A pattern of 270 spots with identical positions was found on every gel; 247 of these spots were not saturated and used for quantitative comparison. Thirty-five, i.e., 14 %, differed significantly in their relative intensity in the two groups. Twenty-eight protein spots were decreased in the Se-deficient group and seven were increased. Sarcomeric creatine kinase M chain, alpha-myosin heavy chain (alpha-MHC) and myosin light chain 1 and 2 (MLC 1 and 2) were largely decreased in Se-deficiency. Three protein spots were increased by more than twofold or appeared only in the Se-deficient group. A mitochondrial creatine kinase was identified in this group. The results suggest that selenium deficiency affects myocardial energy metabolism and contractile proteins. These changes probably reflect non-specific alterations in heart failure.
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PMID:Effects of selenium deficiency on the rat myocardial protein pattern-- investigation by two-dimensional gel electrophoresis. 1087 21

In the failing human myocardium, both impaired calcium homoeostasis and alterations in the levels of contractile proteins have been observed, which may be responsible for reduced contractility as well as diastolic dysfunction. In addition, levels of a key protein in calcium cycling, i.e. the sarcoplasmic reticulum Ca(2+)-ATPase, and of the alpha-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltransferase inhibitor, in normal and pressure-overloaded rat myocardium. We therefore studied, for the first time, the influence of long-term oral application of etomoxir on cardiac function in patients with chronic heart failure. A dose of 80 mg of etomoxir was given once daily to 10 patients suffering from heart failure (NYHA functional class II-III; mean age 55+/-4 years; one patient with ischaemic heart disease and nine patients with dilated idiopathic cardiomyopathy; all male), in addition to standard therapy. The left ventricular ejection fraction was measured echocardiographically before and after a 3-month period of treatment. Central haemodynamics at rest and exercise (supine position bicycle) were defined by means of a pulmonary artery catheter and thermodilution. All 10 patients improved clinically; no patient had to stop taking the study medication because of side effects; and no patient died during the 3-month period. Maximum cardiac output during exercise increased from 9.72+/-1.25 l/min before to 13.44+/-1.50 l/min after treatment (P<0.01); this increase was mainly due to an increased stroke volume [84+/-7 ml before and 109+/-9 ml after treatment (P<0.01)]. Resting heart rate was slightly reduced (not statistically significant). During exercise, for any given heart rate, stroke volume was significantly enhanced (P<0.05). The left ventricular ejection fraction increased significantly from 21.5+/-2.6% to 27.0+/-2.3% (P<0.01). In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties. Thus, although the results of this small pilot study are not placebo-controlled, all patients seem to have benefitted from etomoxir treatment. Etomoxir, which has no acute inotropic or vasodilatory properties and is thought to increase gene expression of the sarcoplasmic reticulum Ca(2+)-ATPase and the alpha-myosin heavy chain, improved clinical status, central haemodynamics at rest and during exercise, and left ventricular ejection fraction.
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PMID:First clinical trial with etomoxir in patients with chronic congestive heart failure. 1088 55

We have developed a transgenic mouse model in which tumor necrosis factor (TNF)-alpha is overexpressed exclusively in the heart under the regulation of the alpha-myosin heavy chain promoter. These animals develop chronic heart failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role of adhesion molecules in mediating cardiac dysfunction in the TNF-alpha transgenic model. TNF-alpha transgenic mice were bred with mice null for intercellular adhesion molecule (ICAM)-1 and P-selectin genes to obtain a lineage of ICAM-1 and P-selectin null mice with selective overexpression of TNF-alpha in the heart. TNF-alpha transgenic animals showed marked upregulation of ICAM-1 mRNA and protein; however, P-selectin mRNA and protein remained undetectable despite chronic TNF overexpression. Cardiac function was markedly improved in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic group versus the ICAM(+/+), P-selectin(+/+), TNF-alpha transgenic group. Kaplan-Meier survival curves showed statistically significant prolonged survival in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic animals. These data suggest that ICAM-1 mediates at least in part the cardiac dysfunction induced by TNF-alpha expression by cardiac myocytes.
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PMID:Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-alpha transgenic mice. 1124 55

Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, alpha-myosin heavy chain promoter (alpha-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5-10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to beta-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.
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PMID:Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. 1124 9

Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardiac function, a transgenic mouse was generated. Cardiac tissue-specific overexpression of the proapoptotic gene Caspase3 was induced by using the rat promoter of alpha-myosin heavy chain, a model that may represent a unique tool for investigating new molecules and antiapoptotic therapeutic strategies. Cardiac-specific Caspase3 expression induced transient depression of cardiac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgenic mice showed increased infarct size and a pronounced susceptibility to die. In this report, we document an unexpected property of the proapoptotic gene caspase3 on cardiac contractility. Despite inducing ultrastructural damage, Caspase3 does not trigger a full apoptotic response in the cardiomyocyte. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpression increases infarct size.
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PMID:Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function. 1149 78


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