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- Lindberg, Erika, 1979
(författare)
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T cell Function in Patients with Dilated Cardiomyopathy
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by dilatation of one or both ventricles together with decreased systolic function. Its etiology is still largely unknown. However, immunological alterations such as the presence of autoantibodies, elevated cytokines in plasma, and viral genomes in the myocardium have been frequently reported. The aim of this thesis was to examine T cell function in patients with DCM. First, cytokines in plasma were measured. In accordance with previous reports, plasma cytokines of TNF-alfa, IL-6, IL-10, and CRP were significantly elevated in patients with heart failure. Incorporating an etiology of DCM or ischemic heart disease together with clinical variables in a multivariate analysis, a diagnosis of DCM was found to be independently associated with lower IL-10 levels. Next, specific CD4+ T cell response, accumulated cytokines in supernatant, and lymphocyte proliferation were measured using flow cytometry-based methods following culture of isolated peripheral blood mononuclear cells, and stimulation with Staphylococcus enterotoxin B or phytohaemagglutinin. The frequency of IFN-gamma-producing CD4+ (Th1) cells was significantly lower in patients than in healthy controls. In contrast, no difference was found in the number of IL-4-producing CD4+ (Th2) cells. In addition, IL-10 production in the supernatant and lymphocyte proliferation were both significantly lower in patients. To conclude, these impairments of IFN-gamma and IL-10 are both consistent with an increased susceptibility to chronic infections and autoimmunity. Finally, we investigated the frequency of a single nucleotide polymorphism in the IFN-gamma gene, which alter the transcription level. We found a significant association between the IFN-gamma polymorphism and susceptibility to DCM. This previously unreported finding could be the first diagnostic marker of a DCM of autoimmune etiology. In its entirety, this thesis supports the concept that DCM is a late sequela of myocarditis leading to a disease of autoimmune character.
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- Scharin Täng, Margareta, 1962, et al.
(författare)
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Cardiac reserve in the transplanted heart: effect of a graft polymorphism in the beta1-adrenoceptor
- 2007
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 26:9, s. 915-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polymorphism of the beta1-adrenoceptor (beta1-AR) affects outcome and beta-blocker efficacy in patients with heart failure. We studied the influence of the beta1-AR Ser49Gly polymorphism on cardiac reserve in transplanted hearts. METHODS: Beta1-AR polymorphism was determined by allelic discrimination analysis. Patients were divided into two groups: either homozygous for Ser49 (n = 15) or with Gly49 in one or both alleles (Gly49; n = 5). Patients underwent a maximal bicycle exercise test and echocardiographic evaluation at rest and during low-dose dobutamine stress. RESULTS: Patients with Gly49 grafts had better physical endurance (144 +/- 26 vs 112 +/- 31 W, p = 0.03), a trend toward better chronotropic reserve (deltaHR 64 +/- 13 vs 47 +/- 16 bpm, p = 0.056) during exercise, and lower resting heart rate (82 +/- 7 vs 90 +/- 7 bpm, p = 0.04) than those homozygous for Ser49. There were no significant differences in left ventricular ejection fraction (LVEF), with the exception of a decrease in cardiac reserve in patients with the Gly49 variants at the lowest dose of dobutamine (deltaLVEF -4.4 +/- 1.5 vs 2.2 +/- 5.8%, p = 0.04). Doppler myocardial tissue velocities of early relaxation were increased in patients with the Gly49 variants compared with patients homozygous for Ser49, both at rest (14.5 +/- 3.2 vs 10.4 +/- 2.0 cm/s, p = 0.03) and during the lowest dose of dobutamine (15.0 +/- 3.7 vs 10.9 +/- 2.5 cm/s, p = 0.04). CONCLUSIONS: Heart transplant patients with the beta1-AR Gly49 variants had a lower heart rate, and better stress endurance and diastolic function compared with patients homozygous for Ser49. They also showed a trend toward better chronotropic reserve. These results provide a possible explanation for differences in cardiac reserve among patients with heart transplants.
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- Scott, Mark G H, et al.
(författare)
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Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins.
- 2006
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Ingår i: Molecular and cellular biology. - 0270-7306. ; 26:9, s. 3432-45
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Tidskriftsartikel (refereegranskat)abstract
- beta-Arrestins (betaarr) are multifunctional adaptor proteins that can act as scaffolds for G protein-coupled receptor activation of mitogen-activated protein kinases (MAPK). Here, we identify the actin-binding and scaffolding protein filamin A (FLNA) as a betaarr-binding partner using Son of sevenless recruitment system screening, a classical yeast two-hybrid system, coimmunoprecipitation analyses, and direct binding in vitro. In FLNA, the betaarr-binding site involves tandem repeat 22 in the carboxyl terminus. betaarr binds FLNA through both its N- and C-terminal domains, indicating the presence of multiple binding sites. We demonstrate that betaarr and FLNA act cooperatively to activate the MAPK extracellular signal-regulated kinase (ERK) downstream of activated muscarinic M1 (M1MR) and angiotensin II type 1a (AT1AR) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr-ERK2 complex formation by FLNA. In Hep2 cells, stimulation of M1MR or AT1AR results in the colocalization of receptor, betaarr, FLNA, and active ERK in membrane ruffles. Reduction of endogenous levels of betaarr or FLNA and a catalytically inactive dominant negative MEK1, which prevents ERK activation, inhibit membrane ruffle formation, indicating the functional requirement for betaarr, FLNA, and active ERK in this process. Our results indicate that betaarr and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization.
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