UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiology of myocardial contractility has been studied for over a century, but only recently has molecular biology provided new insights into the mechanisms responsible for the alterations of contraction and relaxation observed during cardiac hypertrophy and heart failure. Pressure and volume overload produce in the myocyte both qualitative changes characterized by protein isoform switches and quantitative changes characterized by modulation of single genes through a mechanogenic transduction the pathways of which are largely unknown. The qualitative changes involve differential expression of multigene families of contractile proteins, especially myosin heavy chain (MHC) and actin. All situations of pressure overload, or of combined pressure and volume overload activate the beta-MHC gene and deactivate the alpha-MHC one, which leads to a slower, more efficient contraction. In rat, pressure overload transitorily activates the alpha-skeletal actin gene, and both the timing and the distribution of the newly formed beta-MHC and alpha-skeletal actin mRNAs differ. We recently found that the isoactin pattern is the same in patients with end-stage heart failure as that of control human hearts. Moreover, both in rat and human, expression of isomyosins and isoactins are not coordinated, neither during ontogeny nor senescence. All this suggests the existence of several regulatory mechanisms activated during normal cardiac growth or by a mechanical trigger, and preliminary results indicate that it is possible to perform nuclear run-on assays in order to analyze the transcriptional step of these isogenes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart. 138 31

The role of subcellular alterations in the process of heart failure remains ill-defined. Because contractile performance of failing heart muscle is depressed, possible alterations in the myosin molecule could be of particular relevance. There is increasing evidence that myofibrillar ATPase activity is reduced in congestive heart failure, whereas the findings on myosin ATPase are still controversial. The molecular causes of the reduced activity are currently not known. Because alpha-MHC is present only in small amounts in normal ventricles, a shift in favor of beta-MHC is of minor importance. Also immunohistochemical data on subspecies of beta-MHC seem not to provide an explanation. A new type of myosin heterogeneity was found by optimizing native polyacrylamide gel electrophoresis in the presence of pyrophosphate. Two bands (VA and VB) were observed in ventricles of patients with valvular disease. Because the two bands were detected also in normal hearts of large mammals, the existence of VA/VB cannot be diagnostic of diseased heart. However, the VA/VB ratio was influenced by the hemodynamic load, whereby the fast migrating band (VA) increased with the diastolic and systolic load. Because a relationship with the hemodynamic load was observed only in surgical muscle specimens, it appears that this heterogeneity is prone to post mortem modification. Further work is required to identify the molecular nature of this heterogeneity and to examine the therapeutic potential of a pharmacological modification of the VA/VB ratio.
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PMID:Structural and functional diversity of human ventricular myosin. 138 32

Cardiac adaptation to hemodynamic stress involves both quantitative (hypertrophy) and qualitative (pattern of gene expression) changes. Our previous studies have shown that advancing age in the rat is associated with diminished capacity to develop left ventricular hypertrophy in response to either ascending aortic constriction (AoC). In this study, we examined whether the expression of protooncogenes and contractile protein genes in response to AoC differs between adult (9-mo-old) and old (18-mo-old) rats. RNA was isolated from the left ventricles of AoC animals of both age groups subjected to a similar hemodynamic stress. Immediately after AoC, the levels of the ventricular expression of c-fos and c-jun protooncogenes were markedly lower in the old rats than in the adult animals. 5 d after the operation, the ratio of beta- to alpha-myosin heavy chain mRNAs increased significantly after AoC in both age groups. In contrast, AoC was associated with a marked reduction in the levels of mRNAs encoding sarcoplasmic reticulum Ca(2+)-ATPase (by 69%) and cardiac calsequestrin (by 49%) in the old rats but not in the adults. The mRNAs encoding atrial natriuretic factor and skeletal alpha-actin increased in response to AoC only in the adult rats. There were no significant differences in expression of the cardiac alpha-actin mRNA among the experimental groups. These data suggest that (a) the expression of protooncogenes in response to acute pressure overload is significantly reduced in the aged rats and (b) the pattern of expression of the contractile protein gene in response to AoC in the old rats differs qualitatively as well as quantitatively from that in younger animals. These age-related differences may play a role in the higher frequency of heart failure in the aged during hemodynamic stress.
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PMID:Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium. 153 37

Alterations in beta-adrenergic receptor-Gs-adenylyl cyclase coupling underlie the reduced catecholamine responsiveness that is a hallmark of human and animal models of heart failure. To study the effect of altered expression of Gs alpha, we overexpressed the short isoform of Gs alpha in the hearts of transgenic mice, using a rat alpha-myosin heavy chain promoter. Gs alpha mRNA levels were increased selectively in the hearts of transgenic mice, with a level 38 times the control. Despite this marked increase in mRNA, Western blotting identified only a 2.8-fold increase in the content of the Gs alpha short isoform, whereas Gs activity was increased by 88%. The discrepancy between Gs alpha mRNA and Gs alpha protein levels suggests that the membrane content of Gs alpha is posttranscriptionally regulated. The steady-state adenylyl cyclase catalytic activity was not altered under either basal or stimulated conditions (GTP + isoproterenol, GTP gamma S, NaF, or forskolin). However, progress curve studies did show a significant decrease in the lag period necessary for GppNHp to stimulate adenylyl cyclase activity. Furthermore, the relative number of beta-adrenergic receptors binding agonist with high affinity was significantly increased. Our data demonstrate that a relatively small increase in the amount of the coupling protein Gs alpha can modify the rate of catalyst activation and the formation of agonist high affinity receptors.
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PMID:Overexpression of Gs alpha protein in the hearts of transgenic mice. 770 76

Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype-related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal alpha-actin, beta-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular alpha-myosin heavy chain and smooth muscle alpha-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-beta 1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II-induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. 776 70

The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. Our purpose was to determine whether the functional impairment of the failing heart is associated with changes in levels of mRNA encoding proteins that modulate parameters of contraction and relaxation and whether the increased fibrosis observed in the failing heart is related to elevated expression of genes encoding extracellular matrix components. We studied hearts of 18- to 24-month-old spontaneously hypertensive rats with signs and symptoms of heart failure (SHR-F) or without evidence of failure (SHR-NF) and of age-matched normotensive Wistar-Kyoto (WKY) rats. Compared with WKY rats, SHR-NF exhibited left ventricular (LV) hypertrophy (2.2-fold) and right ventricular (RV) hypertrophy (1.5-fold), whereas SHR-F were characterized by comparable LV hypertrophy (2.1-fold) and augmented RV hypertrophy (2.4-fold; all P < .01). Total RNA was isolated from ventricles and subjected to Northern blot analysis. In SHR-F hearts, the level of alpha-myosin heavy chain mRNA was decreased in both ventricles to 1/3 and 1/5 of the SHR-NF and WKY values, respectively (both P < .01). Levels of beta-myosin heavy chain, alpha-cardiac actin, and myosin light chain-2 mRNAs were not significantly altered in hearts of SHR-NF or SHR-F. Levels of alpha-skeletal actin were twofold greater in SHR-NF hearts compared with WKY hearts and were intermediate in SHR-F hearts. Levels of atrial natriuretic factor (ANF) mRNA were elevated threefold in the LV of SHR-NF (P < .05) but were not significantly increased in the RV of SHR-NF compared with WKY rats. During the transition to failure (SHR-F versus SHR-NF), ANF mRNA levels increased an additional 1.6-fold in the LV and were elevated 4.7-fold in the RV (both P < .05). Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SRCA) mRNA were maintained in the LV of hypertensive and failing hearts at levels not significantly different from WKY values. In contrast, the level of RV SRCA mRNA was 24% less in SHR-NF compared with WKY rats, and during the transition to failure, this difference was not significantly exacerbated (29% less than the WKY value). The levels of fibronectin and pro-alpha 1(I) and pro-alpha 1(III) collagen mRNAs were not significantly elevated in either ventricle of the SHR-NF group but were fourfold to fivefold higher in both ventricles of SHR-F (all P < .05).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. 801 79

Cardiac functions are regulated by both contractile proteins and calcium regulatory proteins. In cardiac hypertrophy, an increase in protein synthesis can be partitioned into an increase in both capacity and efficiency of synthesis. beta-cardiac myosin heavy chain (beta-MHC) isoform is predominantly expressed while alpha-MHC is suppressed in pressure overload hypertrophy. The SR Ca(2+)-ATPase is also markedly decreased in pressure overloaded hearts, while in thyrotoxic hearts both are increased. The signal transduction system in cardiac hypertrophy can be examined by stretching cardiac myocytes grown up on deformable membranes. In our analysis, stretching myocytes stimulated protein kinase C, MAP-II kinase and S6 kinase, all of which may lead to the induction of fetal-type cardiac genes and accelerated protein synthesis. Analyses of the subcellular mechanisms of cardiac hypertrophy will provide important insights into understanding of the molecular basis of heart failure.
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PMID:[Molecular basis for heart failure]. 833 89

In the mammalian heart, the development of cardiac hypertrophy is a common feature that normally precedes all forms of heart failure. This adaptive process involves molecular changes in the myocardium, including the altered expression of several genes encoding proteins for contraction and relaxation. The expression of myosin heavy chain (MHC) and sarcomeric alpha-actin messenger ribonucleic acid (mRNA) changes qualitatively during cardiac hypertrophy; however, their accumulations are not coordinated. Skeletal alpha-actin transcripts accumulate throughout the ventricles and earlier than beta-MHC transcripts, which accumulate primarily around large coronary vessels. Skeletal alpha-actin transcripts also "hyperaccumulate" relative to cardiac alpha-actin mRNA, whose expression does not change. Expression of MHC isomRNA shows an inverse relation; as beta-MHC accumulates, alpha-MHC decreases in abundance. From nuclear run-on assays, we present evidence that the accumulation of these gene products is at least under partial transcriptional control with developmental growth, suggesting that those changes that occur with hypertrophy and heart failure may be primarily transcriptionally regulated. The expression of the mRNA for the calcium-adenosine triphosphate (Ca(2+)-ATPase) of the sarcoplasmic reticulum changes quantitatively with cardiac hypertrophy without the reexpression of a different isoform. The relative mRNA and protein concentrations for this protein diminish with both cardiac hypertrophy and heart failure, a change that may partially explain the delayed relaxation rates seen in hypertrophied and failing hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The molecular biology of heart failure. 837 95

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
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PMID:The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. 868 57

Although cardiac failure can develop over time after myocardial infarction, the mechanism responsible for this is still unknown. The change of intracellular Ca2+ transport protein, such as sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), or cardiac phenotypic modulation of contractile protein in noninfarcted myocardium may have a important role. However, the time course in gene expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), and contractile protein in the adjacent and remote noninfarcted myocardium after myocardial infarction has not been examined. At 1, 3 weeks and 3 months after myocardial infarction, hemodynamics were measured and mRNA of the left ventricle was analyzed. Left ventricular end-diastolic volume and weight increased both with time. Ascites became apparent at 3 months after infarction. SR-Ca2+ mRNA levels in the adjacent noninfarcted myocardium were 0.7- (P<0.01), 0.9- (N.S.), and 0.7-fold (P<0.01) of control, and Na+-Ca2+ mRNA levels were 2.1- (P<0.01), 1.4- (P<0.01), and 0.8-fold (P<0.01) of control, at 1, 3 weeks and 3 months after infarction, respectively. beta-Myosin heavy chain (MHC) mRNA was increased to 2.1- (P<0.01), 1.5- (P<0.01), and 1.4-fold (P<0.01), and alpha-skeletal actin was increased to 2.4- (P<0.01), 3.8- (P<0.01), and 1.6-fold (P<0.01) control levels, at 1 week, 3 weeks and 3 months, respectively. In contrast, alpha-MHC mRNA level was decreased at 1 week and 3 months after infarction. alpha-cardiac actin mRNA level did not change over time after infarction. In the remote non-infarcted myocardium, beta-MHC, alpha-skeletal actin, and Na+-Ca2+ mRNA levels were increased, but SR-Ca2+, alpha-MHC, and alpha-cardiac actin mRNA did not change after infarction. These findings suggest that: (1) intracellular Ca2+ handling system after myocardial infarction may be different between adjacent and remote non-infarcted myocardium: and that (2) both decreased gene expression of SR Ca2+-ATPase and Na+-Ca2+ exchanger in the adjacent non-infarcted myocardium may progress cardiac dysfunction.
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PMID:Differences in expression of sarcoplasmic reticulum Ca2+-ATPase and Na+-Ca2+ exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction. 904 40

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