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)

Reactive oxygen species (ROS) have been known to play an important role in the pathogenesis of atherosclerosis and several other cardiovascular diseases. It is now apparent that ROS induce endothelial cell damage and vascular smooth muscle cell (VSMC) growth and cardiac remodeling, which are associated with hypertension, atherosclerosis, heart failure, and restenosis. Several lines of evidence have indicated that ROS and mitogen-activated protein (MAP) kinases were involved in vascular remodeling under various pathological conditions. Recently, it was also reported that MAP kinases were sensitive to oxidative stress. MAP kinases play an important role in cell differentiation, growth, apoptosis, and the regulation of a variety of transcription factors and gene expressions. Bioflavonoids and polyphenolic compounds are believed to be beneficial for the prevention and treatment of atherosclerosis and cardiovascular diseases. One of the most widely distributed bioflavonoids, 3,3',4',5,7-penta-hydroxyflavone (quercetin) and its metabolite quercetin 3-O-beta-D-glucuronide (Q3GA) inhibited Angiotensin II-stimulated JNK activation and resultant hypertrophy of VSMC. Several studies have suggested that various antioxidants including probucol, N-acetyl-L-cysteine, diphenylene iodonium, Trolox C (vitamin E analogue), and vitamin C inhibit VSMC growth, which is associated with pathogenesis of cardiovascular diseases. Therefore, inhibition of MAP kinases by antioxidant treatment may prove to be a therapeutic strategy for cardiovascular diseases. In contrast, some clinical studies have reported that antioxidant vitamins did not show beneficial effects in coronary artery disease or in a number of high-risk people. Thus, further studies are needed to clarify why antioxidants showed beneficial effects in vitro, whereas less satisfactory results were obtained in some clinical conditions.
 ...
PMID:Atheroprotective effects of antioxidants through inhibition of mitogen-activated protein kinases. 1530 27

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.
 ...
PMID:Possible therapeutic targets in cardiac myocyte apoptosis. 1532 Jul 55

Altered cellular adhesion and apoptotic signaling in cardiac remodeling requires coordinated regulation of multiple constituent proteins that comprise cytoskeletal focal adhesions. One such protein activated by cardiac remodeling is related adhesion focal tyrosine kinase (RAFTK, also known as pyk2). Adenoviral-mediated expression of RAFTK in neonatal rat cardiomyocytes involves concurrent increases in phosphorylation of Src, c-Jun N-terminal kinase, and p38 leading to characteristic apoptotic changes including cleavage of poly(ADP-ribose) polymerase, caspase-3 activation, and increased DNA laddering. DNA laddering was decreased by mutation of the Tyr(402) Src-binding site in RAFTK, suggesting a central role for Src activity in apoptotic cell death that was confirmed by adenoviral-mediated Src expression. Multiple apoptotic signaling cascades are recruited by RAFTK as demonstrated by prevention of apoptosis using caspase-3 inhibitor IV (caspase-3 specific inhibitor), PP2 (Src-specific kinase inhibitor), or Csk (cellular negative regulator for Src), as well as dominant negative constructs for p38beta or MKP-1. These RAFTK-mediated phenotypic characteristics are prevented by concurrent expression of wild-type or a phosphorylation-deficient paxillin mutated at Tyr(31) and Tyr(118). Wild-type or mutant paxillin protein accumulation in the cytoplasm has no overt effect upon cell structure, but paxillin accumulation prevents losses of myofibril organization as well as focal adhesion kinase, vinculin, and paxillin protein levels mediated by RAFTK. Apoptotic signaling cascade inhibition by paxillin indicates interruption of signaling proximal to but downstream of RAFTK activity. Chronic RAFTK activation in cardiac remodeling may represent a maladaptive reactive response that can be modulated by paxillin, opening up novel possibilities for inhibition of cardiomyocyte apoptosis and structural degeneration in heart failure.
 ...
PMID:Cardiomyocyte apoptosis triggered by RAFTK/pyk2 via Src kinase is antagonized by paxillin. 1532 13

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.
 ...
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

Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 muM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (1 microM), the A(2A) receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (100 nM), and the A(3) receptor agonist N(6)-(3-iodobenzyl)adenosine-5'-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.
 ...
PMID:Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes. 1545 91

The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism.
 ...
PMID:Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. 1546 32

Gap junction channels form the basis of intercellular communication in the heart. In the working myocardium, the connexin43 (Cx43) is most abundantly found, whereas connexin40 (Cx40) is expressed in the atria and in the conduction system [together with low levels of connexin45 (Cx45)]. However, little is known about the differential regulation of the connexins by pathophysiologically stimuli such as tumor necrosis factor alpha (TNFalpha). Inasmuch as TNFalpha may play a contributory role in the concert of factors involved in the pathophysiology of heart failure and because this cardiac disease often leads to ventricular reentrant arrhythmia, the goal of our study was to find out whether TNFalpha may influence the expression of the cardiac connexins connexin43, connexin40, and connexin45. Neonatal rat cardiomyocytes were exposed to TNFalpha (10, 40, 100, 400, and 1000 pg/ml) for 24 h with or without additional treatment with the mitogenic-activated protein kinase (MAP-kinase) inhibitors SB203580 [4-(4-fluorophenyl)-2-(4-methyl-sulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; 10(-5) M, protein38 mitogenic-activated protein kinase (p38 MAP kinase) inhibitor] or the MEK1 (mitogenic-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 10(-5) M]. Connexin43, connexin40, and connexin45 expressions were analysed using Western blot analysis, immunohistology, and polymerase chain reaction (PCR) studies (connexin43 and connexin40). TNFalpha induced a concentration-dependent increase in connexin43 (by 2.9+/-0.6, P<0.05, n=5) but not in connexin40 or connexin45 expressions. Both connexins (40 and 45) showed a very low expression near the detection limit. The increases in connexin43 expression could be completely suppressed by SB203580 (0.9+/-0.4, P<0.05, n=5) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect connexin43 content. Additional PCR experiments revealed increases in connexin43 mRNA under the influence of 100 pg/ml TNFalpha (211+/-38%, P<0.05, n=5), which could be completely suppressed by SB203580. In contrast, the connexin40 expression remained unchanged. From these results, we conclude that TNFalpha can differentially regulate cardiac connexin expression via p38 MAP kinase pathway and thus may alter intercellular communication. This may contribute to the changes observed in heart failure with regard to the formation of an arrhythmogenic substrate.
 ...
PMID:Chronic regulation of the expression of gap junction proteins connexin40, connexin43, and connexin45 in neonatal rat cardiomyocytes. 1549 89

Mechanical stress on the heart can lead to crucially different outcomes. Exercise is beneficial because it causes heart muscle cells to enlarge (hypertrophy). Chronic hypertension also causes hypertrophy, but in addition it causes an excessive increase in fibroblasts and extracellular matrix (fibrosis), death of cardiomyocytes and ultimately heart failure. Recent research shows that stimulation of physiological (beneficial) hypertrophy involves several signaling pathways, including those mediated by protein kinase B (also known as Akt) and the extracellular-signal-regulated kinases 1 and 2 (ERK1/2). Hypertension, beta-adrenergic stimulation and agonists such as angiotensin II (Ang II) activate not only ERK1/2 but also p38 and the Jun N-terminal kinase (JNK), leading to pathological heart remodeling. Despite this progress, the mechanisms that activate fibroblasts to cause fibrosis and those that differentiate between exercise and hypertension to produce physiological and pathological responses, respectively, remain to be established.
 ...
PMID:The biochemical response of the heart to hypertension and exercise. 1550 80

The removal of damaged, superfluous or energy-starved cells is essential for biological homeostasis, and occurs in every tissue type. Programmed cell death occurs through several closely regulated signal pathways, including apoptosis, in which cell components are broken down and packaged into small membrane-bound fragments that are then removed by neighbouring cells or phagocytes. This process is activated in the cardiac myocyte in response to a variety of stresses, including oxidative and nitrosative stress, and involves mitochondria-derived signals. Loss of cardiac myocytes through apoptosis has been shown to induce cardiomyopathy in a variety of gene-targeted animal models. Because cardiac myocytes have strictly limited ability to regenerate, sustained programmed cell death is likely to contribute to the development and progression of heart failure in a variety of myocardial diseases. At the same time, the cardiac myocyte possesses a number of mechanisms for defence against short-term haemodynamic and oxidative stresses. Our laboratory has recently examined the role of nitric oxide (NO) as a regulator of the programmed death of cardiac myocytes, and the potential contribution of NO and NO-dependent signalling to the loss of myocytes in heart failure. We will review the role of c-Jun N-terminal kinase in response to oxidative and nitrosative stress, and summarise evidence for its role as a cytoprotective mechanism. We will also review evidence implicating NO in the pathophysiology of heart failure, in the context of the extensive and sometimes contradictory body of research on NO and cell survival.
 ...
PMID:Nitric oxide and promotion of cardiac myocyte apoptosis. 1552 66

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.
 ...
PMID:p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload. 1557 67


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