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)

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.
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PMID:Possible therapeutic targets in cardiac myocyte apoptosis. 1532 Jul 55

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) beta1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic d P/d t, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.
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PMID:Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27. 1537 67

The current study investigated the phosphorylation of mitogen-activated protein kinases (MAPKs) as well as pro- and anti-apoptotic proteins in adriamycin (ADR)-induced cardiomyopathy (AIC) and heart failure in rats. Modulatory effects of antioxidant probucol on the activation of MAPKs were also examined. Male rats were administered with ADR (15 mg/kg body wt ip, over 2 wk) with and without probucol (120 mg/kg body wt for 4 wk ip). Hearts from these animals were studied at 1- to 24-h as well as at 3-wk posttreatment durations. In the 3-wk group, ADR depressed cardiac function, increased left ventricular end-diastolic pressure (LVEDP), and caused dyspnea and mortality. These changes were prevented by probucol. Phosphorylation of extracellular signal-regulated kinase (ERK)1/2, in the early stage of AIC, showed a biphasic response, with a maximum increase to 513% seen at 4 h, followed by a decrease to 66.8% at 3 wk after the last injection of ADR. Phosphorylation of p38 and c-Jun NH(2)-terminal kinases (JNKs) showed a steady increase through 2, 4, and 24 h and 3 wk (116% to 148%). In gene microarray analysis at 3 wk (heart failure stage), mRNA expression for both ERK1/2 and p38 kinases was decreased, whereas JNK mRNA was undetectable. Probucol completely prevented these MAPK changes. Activation of caspase-3 as well as the increase in the ratio of Bax to Bcl-xl were seen at early time points (1-24 h) as well as in the heart failure stage (3 wk). It is suggested that a transient increase in ERK1/2 at a shorter interval indicate an early adaptive response, and failure of this response corresponded with heart failure. In contrast, a gradual and persistent increase in p38 and JNK MAPKs as well as in caspase-3 and the Bax-to-Bcl-xl ratio may contribute in the initiation of apoptosis and progression of heart failure. Because probucol modulated changes in cellular signaling pathways and cardiac function, it is likely that oxidative stress plays a key role in AIC and heart failure.
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PMID:Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. 1577 36

Cardiac hypertrophy and heart failure occur in association to alterations in glucose uptake and metabolism. Phenylephrine, among other hypertrophic agonists, has been reported to increase expression of GLUT1 in neonatal rat cardiac myocytes by activating transcription. However, the specific cis- or trans-acting factors in the GLUT1 gene that are targeted by this agonist remain elusive. Here we describe that the activity of the -99/+134 basal promoter of rat GLUT1 is increased by phenylephrine. Nevertheless, this is not mediated by previously described binding sites (GC-box, MG1E) in the promoter. Rather, the TATA box is required by the agonist to activate transcription from the promoter. Interestingly, The Ras-ERK mitogen-activated protein (MAP) kinase pathway is involved in the actions of phenylephrine on GLUT1 transcription, and the effects of Ras on the activity of the promoter depend on the integrity of the TATA box. Our data indicate that phenylephrine induces the expression of the TBP-associated factor TAF(II)250 mRNA, which increases in parallel to the expression of GLUT1, suggesting that altering the expression of basal transcription factors could be one mechanism by which phenylephrine may regulate the activity of the GLUT1 promoter.
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PMID:Phenylephrine requires the TATA box to activate transcription of GLUT1 in neonatal rat cardiac myocytes. 1580 44

The octapeptide angiotensin II (ANG II) can modulate cardiac contractility and is increased in heart failure, where contractile function is impaired. In rat cardiac myocytes, 1 microM of ANG II produces a negative inotropic effect (NIE) (24.6 +/- 5% reduction). However, the subcellular signaling involved in this effect remains elusive. We examined the mechanisms and signaling events involved in the reduction in contractile function induced by the peptide in indo-1-loaded rat cardiomyocytes. The results showed that the NIE of ANG II was not associated with a parallel decrease in the intracellular Ca2+ transient, indicating that a decrease in myofilament responsiveness to Ca2+ underlies the reduction in contractility. We assessed the role of PKC, tyrosine kinases, reactive oxygen species (ROS), and mitogen-activated protein kinases (MAPKs) in the NIE of the peptide. Pretreatment of cells with the NAD(P)H oxidase inhibitor diphenyleneiodonium chloride or with the superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid did not affect the ANG II-induced NIE. Moreover, ANG II-induced ROS production, after 20 min of incubation with the peptide, could not be detected with the use of either the fluorophore 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorecein diacetate or lucigenin-enhanced chemiluminescence. In contrast, the ANG II-induced NIE was abrogated by the inhibitors of PKC (calphostin C), tyrosine kinase (genistein), and p38 MAPK (SB-202190). Furthermore, the NIE was significantly exacerbated (60 +/- 10% reduction) by p38 MAPK overexpression. These results exclude the participation of ROS in the NIE of the peptide and point to PKC and tyrosine kinase as upstream mediators. Furthermore, they reveal p38 MAPK as the putative effector of the reduction in myofilament responsiveness to Ca2+ and the decrease in contractility induced by the peptide.
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PMID:Angiotensin II-induced negative inotropy in rat ventricular myocytes: role of reactive oxygen species and p38 MAPK. 1637 94

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.
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PMID:Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. 1650 6

Large clinical trials have demonstrated that angiotensin-converting-enzyme (ACE) inhibitors are associated with beneficial outcomes in patients with arterial hypertension, heart failure, coronary artery disease, or a combination of these conditions. Other reports have suggested that ACE inhibitors prevent the development or recurrence of atrial fibrillation (AF), a common arrhythmia. In the TRACE trial, in patients with reduced left ventricular function after myocardial infarction, trandolapril reduced the frequency of AF. In the SOLVD trial, a 78% reduction in the frequency of AF after infarction was noted with enalapril compared with placebo. Studies in patients with persistent AF undergoing cardioversion suggest that ACE inhibitors improve outcomes and prevent AF recurrences. The mechanism of AF prevention by ACE inhibitors is unclear, but experimental data show prevention or attenuation of pacing-induced atrial remodeling with ACE inhibitor use. ACE inhibitors decrease angiotensin II concentration; angiotension II stimulates mitogen-activated protein kinases, which in turn activate fibrosis formation and lead to conduction heterogeneity and induction of AF. On the other hand, AF induces atrial dilatation, atrial stretch and atrial secretion of ACE. Among other properties, ACE inhibitors have a sympatholytic effect and increase baroreceptor sensitivity. This review discusses the current data on the use of ACE inhibitors for AF prevention. Although these drugs represent a promising therapeutic option for AF patients, the data so far seem only supportive rather than definitive. Prospective trials are required to validate the benefit of ACE inhibitors and to investigate which patients are most likely to benefit from this pharmacological therapy.
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PMID:Drug Insight: angiotensin-converting-enzyme inhibitors and atrial fibrillation--indications and contraindications. 1656 31

Our previous study demonstrated that norepinephrine (NE) induces endothelial apoptosis mainly through down-regulation of Bcl-2 protein and activation of the beta-adrenergic and caspase-2 pathways. However, whether reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) are involved in this signal transduction remains unknown. Endothelial cells cultured from neonatal rat heart were treated with 100 microM NE. Proteins of MAPKs and Bcl-2 family were assayed by Western blotting. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling assay. ROS was analyzed with flow cytometry. Caspase activity was measured using specific fluorogenic substrates. Treatment with NE increased intracellular ROS level and extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 phosphorylation. Whereas the phosphorylated form of Akt was decreased. The NE-induced apoptosis was abrogated by SP600125 (a specific inhibitor of JNK). Antioxidants such as vitamin C and N-acetyl cysteine inhibited NE-induced ROS production, JNK phosphorylation, caspase activation and apoptosis. Exogenously added superoxide dismutase or catalase markedly diminished NE-induced ROS production and cell death. In conclusions, our study is the first report documenting that NE induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway. Antioxidants may be useful in the prevention and management of NE-mediated endothelial apoptosis during heart failure.
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PMID:Norepinephrine induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway. 1704 59

Reduced activity and expression of endothelial NO synthase (eNOS) is observed in cardiomyocytes from pressure-overloaded hearts with heart failure. The present study was aimed to investigate whether reduced eNOS-derived NO production contributes to the hypertrophic growth and phenotype of these cardiomyocytes. Cultured ventricular cardiomyocytes from adult rats were exposed to Nomega-nitro-l-arginine (l-NNA) to inhibit global NO formation, and cultured cardiomyocytes derived from eNOS-deficient mice were used as a model of genetic knockout of eNOS. Cell growth, formation of oxygen-derived radicals (reactive oxygen species [ROS]), activation of p38 mitogen-activated protein (MAP) kinase phosphorylation, and cytokine expression in cardiomyocytes were investigated. l-NNA caused a concentration-dependent acceleration of the rate of protein synthesis and an increase in cell size. This effect was sensitive to p38 MAP kinase inhibition or antioxidants. l-NNA induced a rapid increase in ROS formation, subsequent activation of p38 MAP kinase, and p38 MAP kinase-dependent increases in the expression of transforming growth factor-beta and tumor necrosis factor-alpha. Similar changes (increased ROS formation, p38 MAP kinase phosphorylation, and cytokine induction) were also observed in cardiomyocytes derived from eNOS+/+ mice when exposed to l-NNA. Cardiomyocytes from eNOS-/- mice displayed higher p38 MAP kinase phosphorylation and cytokine expression under basal conditions, but neither these 2 parameters nor ROS formation were increased in the presence of l-NNA. In conclusion, our data support the hypothesis that reduced eNOS activity in cardiomyocytes contributes to the onset of myocardial hypertrophy and increased cytokine expression, which are involved in the transition to heart failure.
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PMID:Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes. 1707 27

Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. beta-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5alpha (MEK5alpha) (CA-MEK5alpha-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5alpha rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.
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PMID:Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. 1727 11


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