| 1. |
- Tivesten, Åsa, 1969, et al.
(författare)
-
Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice.
- 2002
-
Ingår i: Endocrinology. - 0013-7227. ; 143:11, s. 4235-42
-
Tidskriftsartikel (refereegranskat)abstract
- IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I-/- mice than in control mice. LI-IGF-I-/- mice showed impaired acetylcholine-induced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I-/- mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice.
|
|
| 2. |
- Andersson, Bert, 1952, et al.
(författare)
-
Longitudinal myocardial contraction improves early during titration with metoprolol CR/XL in patients with heart failure.
- 2002
-
Ingår i: Heart (British Cardiac Society). - 1468-201X. ; 87:1, s. 23-8
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate diastolic and systolic left ventricular recovery during titration with metoprolol CR/XL (controlled release/extended release).Placebo run in, followed by an open study.University hospital.14 patients with chronic heart failure.Metoprolol CR/XL titrated from 12.5 mg once daily to 200 mg once daily.M mode recordings of atrioventricular (AV) plane displacement, Doppler measurement of transmitral flow and pulmonary venous flow, two dimensional ejection fraction, and measurement of venous plasma concentration of noradrenaline. Patients were investigated after 2, 4, 6, and 24 weeks of treatment.A reduction of heart rate was observed on the first dose (12.5 mg once daily), from a mean (SD) of 74 (11) to 67 (11) beats/min, p < 0.05. This was accompanied by prominent effects on AV plane filling parameters, including an increase in early diastolic filling period from 87 (28) to 105 (33) ms (p < 0.05), and in the lateral AV plane fractional shortening from 8.7 (2.7)% to 10.2 (2.8)% (p < 0.05). An early trend towards improvement in global systolic left ventricular function was also seen, although this was not significant until six weeks. Ejection fraction increased from 33 (7.5)% to 38 (11)% (p < 0.05).First effects of left ventricular recovery during beta blocker treatment were seen in recordings of longitudinal performance, as expressed by AV plane displacement. Doppler flow dynamics as well as global systolic recovery appeared several weeks later, emphasising the importance of longitudinal performance in evaluating left ventricular function.
|
|
| 3. |
- Larsson, Lisa, 1976, et al.
(författare)
-
Beneficial effect on cardiac function by intravenous immunoglobulin treatment in patients with dilated cardiomyopathy is not due to neutralization of anti-receptor autoantibody
- 2004
-
Ingår i: Autoimmunity. - 0891-6934. ; 37:6-7, s. 489-493
-
Tidskriftsartikel (refereegranskat)abstract
- Anti-beta1-adrenoceptor (beta1AR) autoantibodies have been shown to be pathophysiologically important in idiopathic dilated cardiomyopathy (DCM). Treatment with intravenous immunoglobulin (IVIG) has shown beneficial effects in both DCM and ischemic cardiomyopathy. However, the underlying mechanism has not been clarified. In the present study, we therefore examined whether the improvement of cardiac function was due to neutralization of functional beta1AR autoantibodies by anti-idiotypic antibodies. Autoantibodies against the beta1AR was analysed in sera from patients with DCM and coronary artery disease (CAD) treated with IVIG or placebo before, 6 and 12 months. Six month after treatment, DCM patients showed increase in beta1AR autoantibodies, mostly in IgG1 and IgG2, whereas in CAD patients mostly in IgG2. No changes in beta1AR autoantibodies after 12 months were detected. In summary, our results indicate that improvement of cardiac function by IVIG is not due to neutralization of beta1AR autoantibodies.
|
|
| 4. |
- Mobini, Reza, 1965, et al.
(författare)
-
A monoclonal antibody directed against an autoimmune epitope on the human beta1-adrenergic receptor recognized in idiopathic dilated cardiomyopathy.
- 2000
-
Ingår i: Hybridoma. - : Mary Ann Liebert Inc. - 0272-457X. ; 19:2, s. 135-42
-
Tidskriftsartikel (refereegranskat)abstract
- A monoclonal antibody (MAb M16) was obtained by immunizing Balb/C mice with free peptide H26R, corresponding to the second extracellular loop of the human beta1-adrenergic receptor (beta1AR), against which functional autoantibodies have been detected in patients with idiopathic dilated cardiomyopathy. The MAb was found to be of IgG2b type and directed against a conformational epitope, encompassing the sequence recognized by the human autoantibodies. BIAcore measurements yielded an equilibrium constant of 6.5 X 10(7) M1 with an association rate constant (kon) of 6.5 X 10(4) M(-1) sec(-1) and a dissociation rate constant (koff) of 1.0 X 10(-3) sec(-1). It immunoprecipitated only poorly the solubilized beta1AR of Sf9 cell membranes. Functionally, the MAb was capable of not only reducing the number of the maximal binding sites to the beta1-adrenergic receptor of transfected Sf9 cell membranes, but also of displaying a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These properties, which the MAb shares with the human autoantibodies, makes it an interesting tool for passive transfer studies in mice.
|
|
| 5. |
- Mobini, Reza, 1965, et al.
(författare)
-
Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy.
- 2003
-
Ingår i: Journal of autoimmunity. - 0896-8411. ; 20:4, s. 345-50
-
Tidskriftsartikel (refereegranskat)abstract
- The removal of beta(1)-adrenergic receptor (beta(1)AR) autoantibodies by immunoadsorption (IA) has been proposed as a potential mechanism for the improvement of the left ventricular function in dilated cardiomyopathy (DCM). In the present study, the possible association between removal of the autoantibodies against the human beta(1)AR with the hemodynamic improvement induced by IA was investigated.IA was performed in 22 DCM patients (n=22; NYHA III-IV, EF<30%, stable medication). The beta(1)AR autoantibodies from column eluents (CE) were detected by enzyme-linked immunosorbent assay (ELISA) and BIAcore methods. CE of 32% (7/22) of the patients was found to be antibody-positive with ELISA or BIAcore. In addition, a bioassay system was also used for the detection of this autoantibody. Seventy-three percent (16/22) of the patients were found to be antibody-positive by this method. However, independent of the beta(1)AR antibody detection method, both antibody-positive and antibody-negative groups showed similar acute and prolonged hemodynamic improvements during IA therapy. Furthermore, antibody-positive and -negative groups received a comparable improvement of left ventricular ejection fraction.These results suggest that different mechanisms are involved in the hemodynamic improvement induced by IA. The beneficial hemodynamic effects induced by IA are not directly associated with the removal of beta(1)AR autoantibodies.
|
|
| 6. |
- Mobini, Reza, 1965
(författare)
-
Immunobiochemical mechanisms and pathophysiological significance of β₁-adrenergic receptor autoantibodies in dilated cardiomyopathy
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Idiopathic dilated cardiomyopathy (IDC) is a heart muscle disease of unknown origin and the second most common reason for heart transplantation. Autoimmune processes are involved in the progression of the disease. Circulating autoantibodies against several cardiac proteins have been identified in these patients, e.g. autoantibodies against the b1-adrenergic receptor (b1-AR). The second extracellular loop of the human b1-AR (LII) has been identified as one of the immunogenic targets. The disulfide bridge between the first and the second extracellular loops plays an important role in the receptor activation and signal transduction mechanisms.The focus of this study was to investigate the immunological properties of the extracellular domains of the human b1-AR by raising antipeptide antibodies against the N-terminal, first and second extracellular loops of the receptor. By immunological, pharmacological and cellular physiological studies of these antipeptide antibodies, the second extracellular loop of the receptor was determined to be an important epitope for the receptor recognition and activation. A monoclonal antibody (mAbM16) against this domain was produced. MAbM16 showed a partial agonistic activity by its ability to induce positive chronotropic and inotropic effects on rat cardiomyocytes, effects that were similar to those shown by autoantibodies found in IDC patients. A 10-amino-acid sequence on the Loop II was identified as the specific binding site for the mAbM16. This sequence has been the predominant binding site recognized by affinity-purified autoantibodies from IDC patients.The involvement of anti-b1-AR autoantibodies in IDC as a pathogenic factor has evoked the hypothesis that the removal of these autoantibodies may have beneficial effect in the treatment of IDC. Immunoadsorption (IA) therapy has shown to result in remarkable cardiac improvement in patients with dilated cardiomyopathy (DCM). However, the therapy is nonspecific and the underlying mechanism is unknown. The present study provides evidence for the existence of physiologically active anti-b1-AR autoantibodies in IA-treated DCM patients and shown that the removal of these autoantibodies may have an acute therapeutic effect towards cardiac improvement in DCM patients. The prevalence of anti-b1-AR autoantibodies could act as an immunological marker of the DCM and, in turn, as a mean of evaluating the efficacy of IA therapy. This will unambiguously open new therapeutic approach in IDC.
|
|
| 7. |
|
|
| 8. |
- Omerovic, Elmir, 1968, et al.
(författare)
-
Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.
- 2000
-
Ingår i: Endocrinology. - 0013-7227. ; 141:12, s. 4592-9
-
Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.
|
|
| 9. |
- Staudt, A, et al.
(författare)
-
beta(1)-Adrenoceptor antibodies induce positive inotropic response in isolated cardiomyocytes.
- 2001
-
Ingår i: European journal of pharmacology. - 0014-2999. ; 423:2-3, s. 115-9
-
Tidskriftsartikel (refereegranskat)abstract
- beta(1)-Adrenoceptor autoantibodies are present in approximately 30% of patients suffering from dilated cardiomyopathy. The inotropic effects mediated by these antibodies remain to be studied. Monoclonal antibodies were raised against a peptide corresponding to the second extracellular loop of the human beta(1)-adrenoceptor in balb/C mouse (n=6), and were characterized by enzyme immunoassay after purification by protein A. Purified immunoglobulin G from non-immunized animals (controls) did not influence Ca(2+) transient and cell shortening of rat cardiomyocytes measured by confocal-laser-scanning-microscopy. beta(1)-adrenoceptor antibodies caused a dose-related increase in Ca(2+) transient (dilution 1:2: +35.3+/-5.1%), and in cell shortening (dilution 1:2: +40.5+/-6.3%) (P<0.01 vs. controls). The effect of the beta(1)-adrenoceptor antibodies was blocked by the antigenic peptide and by the antagonist metoprolol. In addition, beta(1)-adrenoceptor antibodies induced a dose-dependent increase of the cyclic adenosine monophosphate. The inotropic response induced by isoproterenol was attenuated by the beta(1)-adrenoceptor antibody. beta(1)-adrenoceptor antibodies as partial agonists induce a specific positive inotropic effect via the protein-kinase-A-cascade.
|
|
| 10. |
- Staudt, Yvonne, et al.
(författare)
-
Beta1-adrenoceptor antibodies induce apoptosis in adult isolated cardiomyocytes.
- 2003
-
Ingår i: European journal of pharmacology. - 0014-2999. ; 466:1-2, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- beta(1)-Adrenoceptor autoantibodies are present in about 30% of patients suffering from dilated cardiomyopathy. The apoptotic effects mediated by beta(1)-adrenoceptor antibodies remain to be studied. Monoclonal antibodies were raised against a synthetic peptide corresponding to the second extracellular loop of the human beta(1)-adrenoceptor in balb/C mouse, and were characterized by enzyme immunoassay. Purified immunoglobulin G from nonimmunized animals (controls) did not influence the rate of apoptosis. beta(1)-Adrenoceptor antibodies caused a dose-related increase in apoptotic cells: annexin test (dilution 1:2: 21+/-1.1% apoptotic cells vs. 4+/-0.4% apoptotic cells in controls; p<0.01); TdT-mediated dUTP nick end labeling (TUNEL) test (dilution 1:2: 26+/-2% apoptotic cells vs. 10+/-2% apoptotic cells in controls; p<0.01). The effect of the beta(1)-adrenoceptor antibodies was blocked by the antigenic peptide and by the antagonist metoprolol (10 micromol/l). The apoptotic effect induced by isoproterenol was attenuated by the beta(1)-adrenoceptor antibody. After pre-incubation of cardiomyocytes with the protein kinase A inhibitor Rp-Adenosine-3',5'-cyclic monophosphothioate triethylamine (RpcAMPS), beta(1)-adrenoceptor antibody was not capable of inducing an increase of the rate of apoptosis. beta(1)-Adrenoceptor antibodies induced apoptosis in adult rat cardiomyocytes via the protein kinase A cascade.
|
|
