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)

Females have a lower incidence of heart failure and improved survival after myocardial ischemia-reperfusion (I/R) compared with males. Although estrogen-suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, it is unclear whether this action is mediated via estrogen receptor beta (ERbeta). Therefore, we hypothesized that ERbeta mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERbeta knockout (ERbetaKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female, but not male, hearts. Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts, which was associated with increased expression of caspase-3 and -8, as well as decreased Bcl-2 levels compared with WT. However, myocardial STAT3, SOCS3 (suppressor of cytokine signaling 3), VEGF, and TNF receptors 1 and 2 levels did not change in ERbetaKO of either sex following I/R. Furthermore, deficiency of ERbeta increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERbeta mediates myocardial protection via upregulation of PI3K/Akt activation, decreased caspase-3 and -8, and increased Bcl-2 in female hearts following I/R. These findings provide evidence of ERbeta-mediated PI3K/Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction.
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PMID:Estrogen receptor beta mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. 1921 25

Diabetic cardiomyopathy is associated with high morbidity and mortality of heart failure. Overactivation of the local chymase-Ang II system plays a dominant role in diabetic cardiomyopathy. Astragalus polysaccharide (APS) is used in traditional Chinese medicine to boost immunity. To study the effect of APS on local system of chymase-Ang II in diabetic cardiomyopathy, we investigated APS/normal saline (NS)-administrated streptozotocin-induced diabetic hamsters. After APS/NS administration at a dose of 1 g/kg per day for 10 weeks, hemodynamic parameters, levels of insulin (INS), C-peptide (C-P), glycosylated serum protein (GSP), lipoproteins, myocardial enzymes, and Ang II (plasma and myocardial) were tested; myocardial collagen (type I and III), myocardial ultrastructure, and activities of matrix metalloproteinase (MMPs) were measured; activities and expression of cardiac chymase and ACE were detected by using quantitative real-time RT-PCR and RIA; protein expression of cardiac phosphoric extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by Western blot. AP-administrated diabetic hamsters had lower levels of GSP, lipoproteins, myocardial enzymes, myocardial Ang II, expression of collagen I and I/ III, activities of pro-MMP-2 and MMP-2, activities and expression of chymase, and expression of p-ERK1/2 than NS-administrated diabetic hamsters and could better protect the myocardial ultrastructure. There was no difference in hemodynamic parameters between two groups. These results indicate that APS could inhibit diabetic cardiomyopathy in hamsters depending on the suppression of the local cardiac chymase-Ang II system.
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PMID:Astragalus polysaccharides inhibited diabetic cardiomyopathy in hamsters depending on suppression of heart chymase activation. 1923 Jul 16

Oxidative stress plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. Because crocetin represses oxidative stress in vitro and in vivo, we have suggested that crocetin would repress cardiac hypertrophy by targeting oxidative stress-dependent signalling. We tested this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. The results showed that crocetin (1-10 microM) dose-dependently blocked cardiac hypertrophy induced by angiogensin II (Ang II; 1 microM) in vitro. Our data further revealed that crocetin (50 mg/kg/day) both prevented and reversed cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardio-graphic parameters and gene expression of hypertrophic markers. The inhibitory effect of crocetin on cardiac hypertrophy is mediated by blocking the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 (MEK/ERK1/2) pathway and GATA binding protein 4 (GATA-4) activation. Further investigation demonstrated that crocetin inhibited inflammation by blocking nuclear factor kappa B (NF-kappaB) signalling and attenuated fibrosis and collagen synthesis by abrogating MEK-ERK1/2 signalling. Overall, our results indicate that crocetin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis by suppression of ROS-dependent signalling pathways.
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PMID:Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. 1941 85

Cell transplantation is an emerging therapy for treating post-infarction heart failure. Although the paracrine effect has been proposed to be an important mechanism for the therapeutic benefits, details remain largely unknown. This study compared various aspects of the paracrine effect after transplantation of either bone marrow mononuclear cells (BMC) or skeletal myoblasts (SMB) into the post-infarction chronically failing heart. Three weeks after left coronary artery ligation, adult rats received intramyocardial injection of either BMC, SMB or PBS only. Echocardiography demonstrated that injection of either cell type improved cardiac function compared to PBS injection. Interestingly, BMC injection markedly improved neovascularization in the border areas surrounding infarcts, while SMB injection decreased fibrosis in both the border and remote areas. Injection of either cell type similarly reduced hypertrophy of cardiomyocytes as assessed by cell-size planimetry using isolated cardiomyocytes. Quantitative RT-PCR revealed that, among 15 candidate mediators of paracrine effects studied, Fgf2 and Hgf were upregulated only after BMC injection, while Mmp2 and Timp4 were modulated after SMB injection. Additional investigations of signalling pathways relevant to heart failure by western blotting showed that p38 and STAT3 were temporarily activated after BMC injection, in contrast, ERK1/2 and JNK were activated after SMB injection. There was no difference in activation of Akt, PKD or Smad3 among groups. These data suggest that paracrine effects observed after cell transplantation in post-infarction heart failure were noticeably different between cell types in terms of mediators, signal transductions and consequent effects.
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PMID:Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure. 1946 39

1. Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure-overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition. 2. Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1-16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)-3beta were determined. 3. Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end-diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation. 4. Following TAC, mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide, beta-myosin heavy chain (MHC) and transforming growth factor-beta1 were increased time dependently, whereas mRNA expression of alpha-MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl-2 were decreased. The ratio of Bcl-2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3beta phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC. 5. In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3beta and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.
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PMID:Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure. 1965 Jul 91

Cardiomyocyte apoptosis is involved in several cardiovascular diseases, including ischemia, hypertrophy and heart failure. Nitric oxide (NO) signalling is crucial in the regulation of cardiomyocyte apoptosis, capable of both inducing and preventing apoptosis depending upon the level of NO production. Growing evidence suggests that NO preconditioning has cardioprotective effects, but the mechanism remains unclear. The purpose of this study was to elucidate how NO preconditioning inhibits subsequent NO-induced apoptosis in H9c2 cells. According to the data, preconditioning with a low concentration of sodium nitroprusside (SNP, 0.3 mM) inhibited subsequent high-concentration-SNP (1.5 mM)-induced apoptosis and this effect was reversed by the protein kinase C (PKC) inhibitor chelerythrine and the cyclooxygenase-2 (COX-2) inhibitor rofecoxib. Low-concentration-SNP-mediated protection involved extracellular signal regulated kinase 1/2 (ERK1/2), a signal transducers and activators of transcription 1/3 (STAT1/3) activation and increased COX-2 expression. Activation of ERK1/2 and STAT1/3 was abolished by chelerythrine. However, COX-2 expression was not inhibited, implying that the COX-2-mediated protective effect occurred via a PKC-independent pathway. The results showed that low-concentration-SNP preconditioning suppresses subsequent high-concentration-SNP-induced apoptosis by ERK1/2-STAT 1/3 activation via PKC-dependent mechanisms in H9c2 cells. COX-2 also plays a role in NO-induced preconditioning, but is independent of PKC.
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PMID:Protective mechanisms of NO preconditioning against NO-induced apoptosis in H9c2 cells: role of PKC and COX-2. 1959 Oct 13

Over the past two decades, basic research has revealed a complex network of regulatory mechanisms that control the ERK1/2-signaling cascade. ERK1/2 mediate cardiac hypertrophy, a major risk factor for the development of arrhythmias, heart failure and sudden death, but also beneficial effects, e.g. protection of the heart from cell death and ischemic injury. Selective targeting of these ambiguous ERK functions could provide a powerful tool in the treatment of cardiac disease. This short review will discuss new mechanistic insights into ERK1/2-dependent development of cardiac hypertrophy and the prospect to translate this knowledge into future therapeutic strategies.
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PMID:Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. 1966 37

The Na(+)-Ca(2+) exchanger gene (Ncx1) is upregulated in hypertrophy and is often found elevated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. beta-Adrenergic receptor (beta-AR) signaling plays an important role in the regulation of calcium homeostasis in the cardiomyocyte, but chronic activation in periods of cardiac stress contributes to heart failure by mechanisms which include Ncx1 upregulation. Here, using a Ca(2+)/calmodulin-dependent protein kinase II (CaMKIIdelta(c)) null mouse, we demonstrate that beta-AR-stimulated Ncx1 upregulation is dependent on CaMKII. beta-AR-stimulated Ncx1 expression is mediated by activator protein 1 (AP-1) factors and is independent of cAMP-response element-binding protein (CREB) activation. The MAP kinases (ERK1/2, JNK and p38) are not required for AP-1 factor activation. Chromatin immunoprecipitation demonstrates that beta-AR stimulation activates the ordered recruitment of JunB homodimers, which then are replaced by c-Jun homodimers binding to the proximal AP-1 elements of the endogenous Ncx1 promoter. In conclusion, this work has provided insight into the intracellular signaling pathways and transcription factors regulating Ncx1 gene expression in a chronically beta-AR-stimulated heart.
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PMID:beta-Adrenergic receptor stimulated Ncx1 upregulation is mediated via a CaMKII/AP-1 signaling pathway in adult cardiomyocytes. 1994 64

The activities and protein content of extracellular signal-regulated kinase (ERK)1/2 in the heart were measured in rats at 4 and 16 weeks after volume overload due to aortocaval shunt. Protein content of phosphorylated ERK1/2 was increased at both 4 and 16 weeks, whereas protein content of total ERK1/2 was increased only at 16 weeks of inducing volume overload. The ERK1/2 activities, estimated as phospho-Elk-1 content, were also increased at 4 and 16 weeks of inducing volume overload. The increased phosphorylated ERK1/2 and E-26-like (Elk)-1 protein content in 16 weeks failing hearts was much greater than that in 4 weeks hypertrophied hearts. These changes in phosphorylated ERK1/2 and Elk-1 protein content in both 4 and 16 weeks volume overloaded animals were attenuated by treatment with enalapril and/or losartan. The results indicate that activation of ERK1/2 may be involved in the development of cardiac hypertrophy and heart failure due to volume overload, and these changes are partially prevented by blockade of the renin-angiotensin system (RAS).
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PMID:Alterations of cardiac ERK1/2 expression and activity due to volume overload were attenuated by the blockade of RAS. 2010 Sep 2

Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca(2+)) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca(2+) release-activated Ca(2+) (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomyocyte store operated Ca(2+) entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth. Employing a combination of siRNA-mediated gene silencing, cultured neonatal rat ventricular cardiomyocytes together with indirect immunofluorescence, epifluorescent Ca(2+) imaging and site-specific protein phosphorylation and real-time mRNA expression analysis, we show for the first time that both Orai1 and Stim1 are present in cardiomyocytes and required for SOCE due to intracellular Ca(2+) store depletion by thapsigargin. Stim1-KD but not Orai1-KD significantly decreased diastolic Ca(2+) levels and caffeine-releasable Ca(2+) from the sarcoplasmic reticulum (SR). Conversely, Orai1-KD but not Stim1-KD significantly diminished basal NRCM cell size, anp and bnp mRNA levels and activity of the calcineurin (CnA) signalling pathway although diminishing both Orai1 and Stim1 proteins similarly attenuated calmodulin kinase II (CamKII) and ERK1/2 activity under basal conditions. Both Orai1- and Stim1-KD completely abrogated phenylephrine (PE) mediated hypertrophic NRCM growth and enhanced natriuretic factor expression by inhibiting G(q)-protein conveyed activation of the CamKII and ERK1/2 signalling pathway. Interestingly, only Orai1-KD but not Stim1-KD prevented Gq-mediated CaN-dependent prohypertrophic signalling. This study shows for the first time that both Orai1 and Stim1 have a key role in cardiomyocyte SOCE regulating both normal and hypertrophic postnatal cardiac growth in vitro.
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PMID:Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. 2013 87


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