| 1. |
- Andersson, Irene, 1978, et al.
(författare)
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Reduced sympathetic responsiveness as well as plasma and tissue noradrenaline concentration in growth hormone transgenic mice
- 2004
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Ingår i: Acta Physiol Scand. - 0001-6772. ; 182:4, s. 369-78
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Acromegaly [overproduction of growth hormone (GH)] and GH deficiency have both been associated with alterations in autonomic nervous system function. The aim of this study was to investigate autonomic nervous system influence on heart rate (HR) in transgenic mice overexpressing bovine GH (bGH). METHODS: HR and HR variability (HRV) were measured in conscious young (8-13 weeks) and old (5-6 months) female bGH and control mice using telemetry. HR control was studied using antagonists and an agonist of adrenergic and muscarinic receptors. Noradrenaline was measured in plasma, heart and kidney using high performance liquid chromatography. RESULTS: Average 24 h resting HR did not differ between bGH and control mice. After saline injection and after muscarinic blockade with methylscopolamine HR increase was blunted (in old) or absent (in young) bGH mice compared with control mice (P < 0.05). Phenylephrine caused a baroreflex mediated decrease in HR from around 550 to 300-350 beats min(-1), not different between bGH and control mice. Time- and frequency-domain measures of HRV were reduced in old bGH compared with control mice (P < 0.05). Noradrenaline concentrations were reduced by 25-49% in plasma and tissue of bGH compared with control mice (P < 0.05). CONCLUSION: The current study suggests reduced autonomic modulation of HR in bGH transgenic mice. Thus, GH appears to have marked effects on autonomic tone, reducing sympathetic nervous system function possibly via reduced noradrenaline stores.
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| 2. |
- Lindblom, Per, 1974, et al.
(författare)
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Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall.
- 2003
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Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 17:15, s. 1835-40
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Tidskriftsartikel (refereegranskat)abstract
- Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display C-terminal protein motifs that confer retention of the secreted factors within the pericellular space. To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice. This resulted in defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria. We conclude that retention of PDGF-B in microvessels is essential for proper recruitment and organization of pericytes and for renal and retinal function in adult mice.
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| 3. |
- Mårdberg, Kristina, 1970, et al.
(författare)
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Basic amino acids as modulators of an O-linked glycosylation signal of the herpes simplex virus type 1 glycoprotein gC: functional roles in viral infectivity.
- 2004
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 14:7, s. 571-81
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Tidskriftsartikel (refereegranskat)abstract
- The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1 is engaged both in viral attachment and viral immune evasion mechanisms in the infected host. Besides several N-linked glycans, gC-1 contains numerous O-linked glycans, mainly localized in two pronase-resistant clusters in the N-terminal domain of gC-1. In the present study we construct and characterize one gC-1 mutant virus, in which two basic amino acids (114K and 117R) in a putative O-glycosylation sequon were changed to alanine. We found that this modification did not modify the N-linked glycosylation but increased the content of O-linked glycans considerably. Analysis of the O-glycosylation capacity of wild-type and mutant gC-1 was performed by in vitro glycosylation assays with synthetic peptides derived from the mutant region predicted to present new O-glycosylation sites. Thus the mutant peptide region served as a better substrate for polypeptide GalNAc-transferase 2 than the wild-type peptide, resulting in increased rate and number of O-glycan attachment sites. The predicted increase in O-linked glycosylation resulted in two modifications of the biological properties of mutant virus-that is, an impaired binding to cells expressing chondroitin sulfate but not heparan sulfate on the cell surface and a significantly reduced plaque size in cultured cells. The results suggested that basic amino acids present within O-glycosylation signals may down-regulate the amount of O-linked glycans attached to a protein and that substitution of such amino acid residues may have functional consequences for a viral glycoprotein involving virus attachment to permissive cells as well as viral cell-to-cell spread.
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| 4. |
- Nyström, Henrik, 1977
(författare)
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Cardiovascular role of PDGF-B in development and disease. Studies in genetically engineered mice
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelet-derived growth factor B (PDGF-B) is vital for microvascular development, and retention of PDGF-B to extracellular matrix (ECM) is important in this process. However, the role and source of PDGF-B in development of macrovascular function is disputed. PDGF-B is also linked to development of vascular proliferative lesions, possibly through interaction with angiotensin II (Ang II) and endothelin-1. We studied the role of PDGF-B in development and disease, using genetically engineered mice and pharmacological inhibitors. For studies on PDGF-B retention, we used the RetKO, a mouse with targeted mutation of the retention motif - a part of the PDGF-B molecule binding to ECM. RetKO displayed primary eutrophic outward remodeling of the aorta, together with microvascular dysfunction, revealed by physical exercise tests. Eccentric cardiac hypertrophy was observed, probably secondary to the microvascular dysfunction. Similar studies were performed in endothelial-specific PDGF B knockout mice (EKO). In EKO, cardiac and macrovascular function was normal, however, physical performance was impaired, probably secondary to microvascular changes. We believe that the normal macrovascular and cardiac function in EKO are due to chimaeric competition resulting from a low recombination frequency, as observed in earlier morphological studies. To study the role of PDGF-B in development of vascular proliferative lesions, we used two mouse models carotid artery ligation as a model for low shear-induced neointimal hyperplasia, and Ang II-induced atherosclerosis in apolipoprotein E knockout mice. In both these models, PDGF-B was upregulated, however, PDGF-receptor beta (PDGFR beta) inhibition (imatinib mesylate, 100 mg/kg/day) had no effect on either plaque formation or neointimal hyperplasia. In Ang II-induced atherosclerosis, endothelin-1 was upregulated, however, unspecific endothelin receptor A/B inhibition (bosentan, 100 mg/kg/day) had no effect on atherosclerosis. Neointimal hyperplasia was accelerated by Ang II, independently of PDGFR-beta. In conclusion, retention of PDGF-B is crucial for development of adequate vascular structure and function. In microvascular development, the source of PDGF-B seems to be the endothelium, however, in macrovessels the source is unclear. No evidence was found for an important pathophysiological role of PDGF-B in Ang II-induced atherosclerosis or low shear-induced neointimal hyperplasia. However, Ang II exerted an accelerating effect on lesion progression in both these models.
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