| 1. |
- Baba, Akiyasu, et al.
(författare)
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Antigen-specific effects of autoantibodies against sarcolemmal Na-K-ATPase pump in immunized cardiomyopathic rabbits.
- 2006
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Ingår i: International journal of cardiology. - : Elsevier BV. - 0167-5273. ; 112:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We examine antigen-specific actions of autoantibodies directed against sarcolemmal Na-K-ATPase. BACKGROUND: Autoantibodies against some receptors or pumps were detected in patients with dilated cardiomyopathy. Although immunoglobulin adsorption therapy improved cardiac function in such patients, direct pathogenic effects of autoantibodies remain to be proven. METHODS: Japanese white rabbits were immunized once a month with purified Na-K-ATPase (NKA rabbits, n=10) or a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta rabbits, n=10), respectively. Control rabbits (n=10) received vehicle in the same manner. RESULTS: At 6 months, cardiac hypertrophy along with increased left ventricular end-diastolic pressure was observed in both NKA and beta rabbits, and inhibitory G protein level increased in both NKA and beta rabbits. Histological findings showed similar myocyte hypertrophy and interstitial fibrosis in both rabbits. Enzymatic activities of Na-K-ATPase were lower in NKA rabbits than in other groups. Immunoblotting showed that alpha3-isoform of Na-K-ATPase was selectively reduced in myocardium from NKA rabbits. CONCLUSIONS: Our present findings suggested that isoform-specific alterations of myocardial Na-K-ATPase activity were induced by immunizing rabbits. This was not secondary change due to cardiac hypertrophy. Thus, autoantibodies against sarcolemmal Na-K-ATPase have antigen-specific effect on the heart in vivo.
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| 2. |
- Baba, Akiyasu, et al.
(författare)
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Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy.
- 2004
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X. ; 25:13, s. 1108-15
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To characterise the clinical significance of M2-muscarinic acetylcholine receptor autoantibodies (M2-AAB) in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: Sera from 104 patients with DCM, age-matched with 104 patients with idiopathic atrial fibrillation (Af) and 104 healthy control subjects, were screened for M2-AAB by enzyme-linked immunosorbent assay (ELISA). IgG purified by Protein-A column was also used as a primary antibody in ELISA. In DCM, M2-AAB were detected in 40% of patients using whole sera and in 36% of patients using purified IgG. M2-AAB were also found in several patients with idiopathic Af (23%, 23%), and these frequencies were significantly higher than those in healthy subjects (8%, 8%). Af was more common in AAB-positive than in AAB-negative patients with DCM. Multivariable analysis confirmed that M2-AAB were independent predictors of the presence of Af in such patients. We determined electrophysiological changes by adding patient purified M2-AAB to chick embryos. Purified IgG from both Af and DCM patients exhibited negative chronotropic effects and induced supraventricular arrhythmias. CONCLUSION: M2-AAB may play a role in mediating the development of Af in patients with DCM.
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| 3. |
- Bkaily, Ghassan, et al.
(författare)
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Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.
- 2003
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Ingår i: Canadian journal of physiology and pharmacology. - : Canadian Science Publishing. - 0008-4212 .- 1205-7541. ; 81:3, s. 234-46
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Tidskriftsartikel (refereegranskat)abstract
- The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.
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| 4. |
- Bollano, Entela, 1970, et al.
(författare)
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Cardiac remodeling rather than disturbed myocardial energy metabolism is associated with cardiac dysfunction in diabetic rats.
- 2006
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Ingår i: Int J Cardiol. - : Elsevier BV. - 0167-5273.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Diabetes mellitus (DM) alters the energy substrate metabolism in the heart and the early sign of diabetic cardiomyopathy is the diastolic dysfunction. Although it is known that the extracellular matrix must be altered in the presence of diabetes, its local regulation has not been fully elucidated. Our aim was to evaluate in vivo left ventricular (LV) structure; function and bioenergetics in streptozotocin (STZ) induced diabetes mellitus. METHODS: Cardiac function was evaluated using echocardiography in anesthetized Sprague-Dawley rats 12 weeks after injection of STZ and in age-matched control rats before and after atrial pacing. In vivo (31)P magnetic resonance spectroscopy was done to measure the phosphocreatine (PCr) to ATP ratio. Myocardial protein expression of metalloproteinases MMP-2, -9, tissue inhibitor TIMP-1, -2 and collagen was measured using Western blot. RESULTS: Bodyweight (BW) was decreased in diabetic rats. Heart weight/BW and LV mass/BW ratios were higher in diabetic animals compared to controls (2.3+/-08 vs 2.1+/-08 mg/g p<0.05). Heart rate was lower in diabetic rats (293+/-20 vs 394+/-36 bpm p<0.05). The velocity of circumferential shortening and peak aortic velocity were lower in diabetic animals and were more pronounced during atrial pacing. The basal PCr/ATP ratio was not different in the two groups. Total collagen was higher in diabetic rats (3.8+/-0.3 vs 2.9+/-01 mg/g, p<0.05). Protein expression of MMP-2 was significantly diminished in diabetic rats by approximately 60%, while MMP-9, TIMP-1 and -2 were unchanged. CONCLUSION: Streptozotocin induced diabetes led to increased LV/bodyweight, increased collagen content, and diminished MMP-2 with no change in PCr/ATP. Therefore, remodeling rather than disturbed energetics may underlie diabetic cardiomyopathy.
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| 5. |
- Bollano, Entela, 1970, et al.
(författare)
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Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene.
- 2000
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Ingår i: Endocrinology. - 0013-7227. ; 141:6, s. 2229-35
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.
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| 6. |
- Buvall, Lisa, 1976, et al.
(författare)
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Antibodies against the beta1-adrenergic receptor induce progressive development of cardiomyopathy
- 2007
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Ingår i: J Mol Cell Cardiol. - : Elsevier BV. - 0022-2828. ; 42:5, s. 1001-7
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Tidskriftsartikel (refereegranskat)abstract
- Different immune disturbances have been found among patients with dilated cardiomyopathy (DCM), including antibodies directed against different cardiac antigens, such as the second extracellular loop of the beta(1)-adrenergic receptor. The aim of our study was to investigate antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor effect on cardiac functions at an early and late stage during DCM development. This was made in a mouse model, in which DCM was induced by immunization with the second extracellular loop of the beta(1)-adrenergic receptor. Mice were immunized for 14 or 25 weeks respectively with the second extracellular loop of the beta(1)-adrenergic receptor. At 14 weeks, there was no decreased heart function reviled by echocardiography at rest, but when dobutamine stress echocardiography was used, a lower cardiac reserve was shown in the mice with antibodies against the second extracellular loop of the beta(1)-adrenergic receptor. By 25 weeks, decreased heart function, dilatation of the left ventricle and thinner left ventricular posterior wall were observed. Further biochemical analyses at 25 weeks showed increased mRNA expressions for beta(1)-adrenergic receptor kinase, monocyte chemoattractant protein-1 and the brain natriuretic peptide as well as increased concentrations of complement factor 3 in sera in the immunized animals. Our data suggest a cardiotoxic effect of antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor and a capacity to induce DCM with progressive remodeling, decreased cardiac function, altered beta(1)AR signaling and upregulation of proinflammatory components.
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| 7. |
- Buvall, Lisa, 1976, et al.
(författare)
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Phenotype of early cardiomyopathic changes induced by active immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the human beta-adrenergic receptor
- 2006
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Ingår i: Clin Exp Immunol. - : Oxford University Press (OUP). - 0009-9104. ; 143:2, s. 209-15
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Tidskriftsartikel (refereegranskat)abstract
- In the failing human heart, due to idiopathic dilated cardiomyopathy, it has been suggested that the beta1-adrenergic receptor (beta1AR) is a potential pathogenic autoantigen. The aim of the present study was to investigate whether immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the beta1AR (beta1AR EC(II)) was able to induce the early stage of cardiomyopathy and also to investigate immunological and receptor functional parameters at a transcriptional level to permit insights into the autoimmune mechanism in cardiomyopathy. Eleven Whistar Fur rats were immunized with a beta1AR EC(II) peptide (H26R) once a month during 12 months and seven control rats were injected with vehicle according to the same procedure used for the immunized group. Cardiac function, beta1AR autoantibodies and their functional effects on cardiomyocytes were analysed. beta1AR receptor signalling, immunological and cardiomyocyte stretch markers were determined on transcriptional level. In H26R immunized rats, beta1AR autoantibodies were shown to be present and functionally active, cardiac functions in terms of fractional shortening were decreased and beta1-adrenergic receptor kinase (GRK2) mRNA were increased compared with the control group. These data have shown that immunization of rats with a putative antigenic peptide was able to induce an early stage phenotype of cardiomyopathy in the form of cardiac dysfunction and up-regulation of GRK2 as the first step in the desensitization process of the beta1AR, implying the pathological importance of the beta1AR autoantibody.
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| 8. |
- Chen, Jie, et al.
(författare)
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Effects of autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy on neonatal rat cardiomyocytes
- 2006
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Ingår i: The European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 8:5, s. 460-467
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Immunoadsorption has been shown to improve cardiac performance and reduce mortality in patients with dilated cardiomyopathy. In this study, the underlying mechanism for these beneficial effects was investigated in cultured rat cardiomyocytes. METHODS AND RESULTS: Immunoadsorption was performed in patients with dilated cardiomyopathy (n=7). Antibody-induced complement-dependent cytotoxicity was investigated by colorimetric MTT. Autoantibodies against the beta(1)-adrenoceptor were detected by ELISA and purified. Column eluent from six patients exhibited a cytotoxic effect, three patients were positive for the beta(1)-adrenoceptor autoantibodies. The purified autoantibodies were able to visualize the beta(1)-adrenoceptors by immunocytofluorescence on rat cardiomyocytes, and also displayed partial agonist properties and induced a positive chronotropic effect, which were blocked by the beta(1)-selective antagonist bisoprolol and the peptide corresponding to the beta(1)-adrenoceptor. Column eluent from one patient induced apoptosis in nick end labelling test (8.1+/-1.7% vs. 2.9+/-1.2% in control, p<0.05). CONCLUSION: Autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy have a pathophysiological role, as shown by the complement-dependent cytotoxicity and chronotropic action on rat cardiomyocytes. This implies that removal of circulating autoantibodies might be part of the underlying mechanism for improved cardiac function.
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| 9. |
- Fu, Michael, 1963, et al.
(författare)
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Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.
- 2000
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Ingår i: Journal of hypertension. - 0263-6352. ; 18:7, s. 945-53
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Tidskriftsartikel (refereegranskat)abstract
- Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.
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| 10. |
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