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)

In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M2-subtype that couple via a pertussis toxin-sensitive Gi-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as beta-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac Gi-activity is increased.
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PMID:Muscarinic receptors in the failing human heart. 1044 75

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.
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PMID:Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. 1053 53

Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.
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PMID:Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury. 1057 39

1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the beta3-adrenoceptor and termed the putative beta4-adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of beta-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1+/-0.6 mN, n=10; MI 2.1+/-0.4 mN, n=8, P<0.02), RO 363 by 61% (sham 4.2+/-0.5 mN, n=10; MI 1.8+/-0.3 mN, n=8, P<0.005) and CGP 12177A by 49% (sham 1.4+/-0.1 mN, n=5; MI 0.7+/-0.2 mN, n=7, P<0.05) in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC50: sham 8.79+/-0.08, n=10; MI 8.30+/-0.10, n=8; P=0.001) and RO 363 (pEC50: sham 8.69+/-0.07, n=10; MI 8.33+/-0.10, n=8; P<0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 microg kg-1, i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5+/-0.5 mN, n=9; MI 3.2+/-0.6 mN, n=11, P=0.702) and CGP 12177A (sham 1.6+/-0.3 mN, n=6; MI 1.9+/-0.4 mN, n=7, P=0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pKB: LA 6.7+/-0.2, n=6; RA 7. 1+/-0.1, n=4), ICI 118,551 (pKB: LA 6.4+/-0.1, n=5; RA 6.3+/-0.1, n=6), propranolol (pKB: LA 6.6+/-0.1, n=5; RA 6.8+/-0.1, n=6) and bupranolol (pKB: LA 7.2+/-0.1, n=6; RA 7.7+/-0.1, n=8), showed moderate affinity for the putative beta4-adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the beta1- and putative beta4-adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at beta1-adrenoceptors also interact with putative beta4-adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the beta1-adrenoceptor.
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PMID:Desensitization and resensitization of beta 1- and putative beta 4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure. 1060 18

Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this betaAR dysfunction was explored in transgenic mice overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6 versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels. Functional coupling of both betaAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these mice showed decreased formation of the active high-affinity conformation (R(H) = 29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C), only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V adenylyl cyclase was decreased approximately 45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq) mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by in vivo G(q) signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased G(alphaq) signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered.
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PMID:Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction. 1064 37

We present a four-month-old girl with severe hemolytic anemia and reticulocytopenia. This case is the youngest with hemolytic anemia encountered in our hospital. Findings of autoimmune hemolytic anemia were preceded by diphtheria-pertussis-tetanus (DPT) and oral polio vaccines which were given one month before. At admission, she had heart failure, her hemoglobin (Hb) was 27 gm/L, hematocrit (Hct) 8.5 percent, reticulocyte count 0.2 percent, and gamma and non-gamma Coombs tests were positive. Plasma Hb was 23 percent (N < 3%) and haptoglobin 0 mg/dl. Bone marrow aspiration smear revealed erythroid hyperplasia. No infection, immunodeficiency or malignancy could be established. She received multiple transfusions and did not respond to methyl prednisolone therapy of seven days' duration, but was successfully treated with a combination of immunosuppressive therapy (cyclophosphamide, 6-mercaptopurine, intravenous immunoglobulin and prednisolone, which was added later). This case is interesting in that the disease was preceded by DPT vaccination, was associated with reticulocytopenia and was resistant to steroids.
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PMID:A warm antibody mediated acute hemolytic anemia with reticulocytopenia in a four-month-old girl requiring immunosuppressive therapy. 1077 Jun 64

A fetus with the sonographic appearance of echogenic and enlarged lungs and dilated trachea and bronchi, indicating laryngotracheal obstruction, is reported. Additionally, the fetus had ascites and subcutaneous edema and the amniotic fluid volume was reduced. Doppler flow investigation of the systemic venous circulation revealed signs of heart failure, and color Doppler visualized possible increased pulmonary flow. Following termination of pregnancy, autopsy confirmed the sonographic observations and revealed a hypoplastic thymus. During the present pregnancy the mother suffered from sustained cough, and serological tests revealed acute pertussis infection. Polymerase chain reaction investigation for Bordetella pertussis in the amniotic fluid was negative. The possibilities of pertussis toxins as noxious factors and of an atypical presentation of DiGeorge anomaly are discussed.
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PMID:Prenatal diagnosis of tracheal obstruction: possible association with maternal pertussis infection. 1077 17

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.
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PMID:Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. 1082 15

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.
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PMID:Src and Rac mediate endothelin-1 and lysophosphatidic acid stimulation of the human brain natriuretic peptide promoter. 1123 Mar 22

The beta2-adrenergic receptor (beta2-AR)-mediated increase in cardiac L-type Ca2+ current (I(Ca,L)) has been documented in normal subjects. However, the role and mechanism of beta2-AR activation on I(Ca,L) in heart failure (HF) are unclear. Accordingly, we compared the effect of zinterol (ZIN), a highly selective beta2-AR agonist, on I(Ca,L) in isolated left ventricular cardiomyocytes obtained from normal control and age-matched rats with HF induced by left coronary artery ligation (4 months). I(Ca,L) was measured by using the whole-cell voltage-clamp technique. In normal myocytes, superfusion of ZIN (10(-5) M) caused a 21% increase in I(Ca,L) (9.21 +/- 0.24 versus 7.59 +/- 0.20 pA/pF) (p < 0.05). In HF myocytes, the same concentration of ZIN produced a significantly greater increase (30%) in I(Ca,L) (6.20 +/- 0.24 versus 4.75 +/- 0.17 pA/pF) (p < 0.01). This ZIN-induced increase in I(Ca,L) was further augmented in both normal and HF myocytes (normal: 59 versus 21%; HF: 71 versus 30%) after the incubation of myocytes with pertussis toxin (PTX, 2 microg/ml, 36 degrees C, 6 h). These effects were not modified by the incubation of myocytes with CGP-20712A (3 x 10(-7) M), a beta1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551 (10(-7) M), a beta2-AR antagonist. In addition, all of the effects induced by ZIN were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (100 microM, in the patch-pipette solution). In conclusion, beta2-AR activation stimulates L-type Ca2+ channels and increases I(Ca,L) in both normal and HF myocytes. In HF, beta2-AR activation-induced augmentation of I(Ca,L) was increased. These effects are likely to be mediated through a cAMP-dependent mechanism and coupled with both stimulatory G protein and PTX-sensitive G protein.
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PMID:Enhanced cardiac L-type calcium current response to beta2-adrenergic stimulation in heart failure. 1140 41


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