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)

Of the many symposia at the 28th World Congress of the International Society of Heart Research, held August 7-10, 2004, in Queensland, Australia, this report covers the following: understanding the basic mechanisms of cardiac arrhythmias; unstable plaque; innate immunity in cardiovascular health and disease; matrix metalloproteinases; defining the targets for treatment of heart failure; NAD(P)H oxidase-derived reactive oxygen species--signaling or stress; expanding roles for alpha(1)-adrenoceptors in the cardiovascular system; estrogen derivatives in cardiovascular disease--old questions, new answers; and p38 MAPK: a kind or callous kinase. Lectures on the use of gene therapy for cardioprotection and antiarrhythmic actions of calmodulin kinase inhibition, and selected poster presentations are also discussed.
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PMID:Recent advances in heart research. 1575 77

The nonreceptor protein tyrosine kinase (PTK) proline-rich tyrosine kinase 2 (PYK2) has been implicated in cell signaling pathways involved in left ventricular hypertrophy and heart failure, but its exact role has not been elucidated. In this study, replication-defective adenoviruses (Adv) encoding green fluorescent protein (GFP)-tagged, wild-type (WT), and mutant forms of PYK2 were used to determine whether PYK2 overexpression activates MAPKs, and downregulates SERCA2 mRNA levels in neonatal rat ventricular myocytes (NRVM). PYK2 overexpression significantly decreased SERCA2 mRNA (as determined by Northern blot analysis and real-time RT-PCR) to 54 +/- 4% of Adv-GFP-infected cells 48 h after Adv infection. Adv-encoding kinase-deficient (KD) and Y(402)F phosphorylation-deficient mutants of PYK2 also significantly reduced SERCA2 mRNA (WT>KD>Y(402)F). Conversely, the PTK inhibitor PP2 (which blocks PYK2 phosphorylation by Src-family PTKs) significantly increased SERCA2 mRNA levels. PYK2 overexpression had no effect on ERK1/2, but increased JNK1/2 and p38(MAPK) phosphorylation from fourfold to eightfold compared with GFP overexpression. Activation of both "stress-activated" protein kinase cascades appeared necessary to reduce SERCA2 mRNA levels. Adv-mediated overexpression of constitutively active (ca)MKK6 or caMKK7, which activated only p38(MAPK) or JNKs, respectively, was not sufficient, whereas combined infection with both Adv reduced SERCA2 mRNA levels to 45 +/- 12% of control. WTPYK2 overexpression also significantly reduced SERCA2 promoter activity, as determined by transient transfection of a 3.8-kb SERCA2 promoter-luciferase construct. Thus a PYK2-dependent signaling cascade may have a role in abnormal cardiac Ca(2+) handling in left ventricular hypertrophy and heart failure via downregulation of SERCA2 gene transcription.
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PMID:PYK2 regulates SERCA2 gene expression in neonatal rat ventricular myocytes. 1582 61

The hypothesis that intracrine renin-angiotensin system activated during heart failure is part of the tendency of the heart to return to embryological conditions when organogenesis is possible is presented and discussed. The hypothesis proposes that the change in genetic makeup, which is known to occur during heart failure, includes a drastic change of intercellular chemical and electrical communication such as second messengers and other signal molecules which are involved in cell proliferation and growth. The role of angiotensin II, which is a growth factor, reduces cell coupling in the failing heart through the activation of AT1 receptors and intracellular pathways, such as PKC, MAPK family and increment of intracellular calcium, might play a key role in the genetic reprogramming of the failing heart.
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PMID:Cardiac intracrine renin angiotensin system. Part of genetic reprogramming? 1632 80

Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. Since its discovery, serum and tissue AM expression have been shown to be increased in experimental models and in patients with cardiac hypertrophy, myocardial infarction and end-stage heart failure with several beneficial effects. Considerable evidence exists for a wide range of autocrine, paracrine and endocrine mechanisms for AM which include vasodilatory, anti-apoptotic, angiogenic, anti-fibrotic, natriuretic, diuretic and positive inotropic. Thus, through regulation of body fluid or direct cardiac mechanisms, AM has additive and beneficial effects in the context of heart disease. Notable molecular mechanisms of AM include cyclic adenosine monophosphate, guanosine-3',5'-monophosphate, PI3K/Akt and MAPK-ERK-mediated cascades. Given the endogenous and multifunctional nature of AM, we consider this molecule to have great potential in the treatment of cardiovascular diseases. In agreement, early experimental and preliminary clinical studies suggest that AM is a new and promising therapy for cardiovascular diseases.
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PMID:Adrenomedullin: molecular mechanisms and its role in cardiac disease. 1658 14

Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
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PMID:The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. 1680 Jul 27

Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium.
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PMID:Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. 1700 95

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts (n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg.ml(-1).min(-1) x 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1beta and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 +/- 4.5% vs. WT 22 +/- 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 +/- 6.4% vs. WT 45 +/- 8.8%). IL-6 was decreased in TNFR1KO (150.2 +/- 3.65 pg/mg protein) versus WT (211.4 +/- 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1beta following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta.
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PMID:Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta. 1711 46

We hypothesized that the histamine H(3)-receptor (H(3)R)-mediated attenuation of norepinephrine (NE) exocytosis from cardiac sympathetic nerves results not only from a Galpha(i)-mediated inhibition of the adenylyl cyclase-cAMP-PKA pathway, but also from a Gbetagamma(i)-mediated activation of the MAPK-PLA(2) cascade, culminating in the formation of an arachidonate metabolite with anti-exocytotic characteristics (e.g., PGE(2)). We report that in Langendorff-perfused guinea-pig hearts and isolated sympathetic nerve endings (cardiac synaptosomes), H(3)R-mediated attenuation of K(+)-induced NE exocytosis was prevented by MAPK and PLA(2) inhibitors, and by cyclooxygenase and EP(3)-receptor (EP(3)R) antagonists. Moreover, H(3)R activation resulted in MAPK phosphorylation in H(3)R-transfected SH-SY5Y neuroblastoma cells, and in PLA(2) activation and PGE(2) production in cardiac synaptosomes; H(3)R-induced MAPK phosphorylation was prevented by an anti-betagamma peptide. Synergism between H(3)R and EP(3)R agonists (i.e., imetit and sulprostone, respectively) suggested that PGE(2) may be a downstream effector of the anti-exocytotic effect of H(3)R activation. Furthermore, the anti-exocytotic effect of imetit and sulprostone was potentiated by the N-type Ca(2+)-channel antagonist omega-conotoxin GVIA, and prevented by an anti-Gbetagamma peptide. Our findings imply that an EP(3)R Gbetagamma(i)-induced decrease in Ca(2+) influx through N-type Ca(2+)-channels is involved in the PGE(2)/EP(3)R-mediated attenuation of NE exocytosis elicited by H(3)R activation. Conceivably, activation of the Gbetagamma(i) subunit of H(3)R and EP(3)R may also inhibit Ca(2+) entry directly, independent of MAPK intervention. As heart failure, myocardial ischemia and arrhythmic dysfunction are associated with excessive local NE release, attenuation of NE release by H(3)R activation is cardioprotective. Accordingly, this novel H(3)R signaling pathway may ultimately bear therapeutic significance in hyper-adrenergic states.
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PMID:Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway. 1726 40

Among the multiple cardiac manifestations occurring in HIV-infected patients, cardiomyopathy is one of the most challenging. Its incidence has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART). Also, its pathogenesis remains relatively unclear. Although several studies demonstrated the presence of HIV genome in the heart of patients, more recent developments found that viral infection plays an indirect role only, as well as they recognized the contribution of proinflammatory cytokines in the progression of the disease. Experimental studies on animals and cultured myocytes have established the signalling pathway triggered by proinflammatory cytokines in heart failure and cardiomyopathy. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 promote expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes through activation of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB (NFkappaB). TNF-alpha and high concentrations of NO also induce cardiomyocyte apoptosis by TNF type 1 receptor activation. This biological framework, which is also involved in progression of cardiomyopathy in humans, is more pronounced in HIV-infected patients, in whom proinflammatory cytokines TNF-alpha, IL-1 and IL-6 are increased, resulting in an enhanced expression of cardiac iNOS, especially in patients with a low CD4 T cell count. This may account for the worse outcome of heart failure in HIV-infected patients. However, there are only few data today to support future therapeutic implications of cytokines antagonism in treatment of HIV-infected patients with cardiomyopathy. Whether modulation of TNF production or selective inhibition of p38 MAPK pathway could be useful approaches remains uncertain.
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PMID:Cytokines in HIV-associated cardiomyopathy. 1733 7

The objective of this study was to understand the mechanism of action of nitric oxide (NO) in the heart by determining whether nitric oxide (NO) released from sodium nitroprusside (SNP) induces p38 mitogen activated protein kinase (p38 MAPK) phosphorylation and whether this is mediated through a cyclic GMP (cGMP)/protein kinase G (PKG) pathway. p38 MAPK activation was examined by Western blotting of whole cell lysates of embryonic chick cardiomyocytes with antibodies specific to the native or phosphorylated forms of p38 MAPK. SNP, 1 mM, which released significant amounts of NO as determined by Griess reaction, induced p38 MAPK phosphorylation that was apparent within 10 min, was significantly (p<0.05) greater than control at 60 min and remained higher than initial levels up to the 4 h end point of the experiment. This could not be attributed to hydrogen peroxide release from SNP as catalase did not affect SNP-induced p38 MAPK phosphorylation. SB202190, a relatively selective inhibitor of p38 MAPK, mainly p38alpha MAPK, inhibited SNP-induced p38 MAPK phosphorylation. SNP-induced p38 MAPK phosphorylation was not altered by pre-treatment with the PKG inhibitor KT 5823 or by ODQ a potent and selective inhibitor of NO-sensitive guanylyl cyclase. p38 MAPK phosphorylation was not induced by the cell permeable cGMP analogue, 8-Br-cGMP. In summary, considering that new therapeutic strategies aimed at NO and p38 MAPK are being considered for myocardial injury and heart failure, these data demonstrate that SNP induces p38 MAPK phosphorylation through a pathway that is independent of NO-induced activation of cGMP/PKG pathways and suggest that non cGMP/PKG regulatory proteins leading to p38 MAPK phosphorylation merit further investigation to address this therapeutic target.
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PMID:Sodium nitroprusside activates p38 mitogen activated protein kinase through a cGMP/PKG independent mechanism. 1770 40


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