| 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. |
- Hernebring, Malin, 1978, et al.
(författare)
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Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28
- 2013
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 3:3, s. artikel nr 1381-
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Tidskriftsartikel (refereegranskat)abstract
- In embryonic stem cells, removal of oxidatively damaged proteins is triggered upon the first signs of cell fate specification but the underlying mechanism is not known. Here, we report that this phase of differentiation encompasses an unexpected induction of genes encoding the proteasome activator PA28 alpha beta (11S), subunits of the immunoproteasome (20Si), and the 20Si regulator TNF alpha. This induction is accompanied by assembly of mature PA28-20S(i) proteasomes and elevated proteasome activity. Inhibiting accumulation of PA28 alpha using miRNA counteracted the removal of damaged proteins demonstrating that PA28 alpha beta has a hitherto unidentified role required for resetting the levels of protein damage at the transition from self-renewal to cell differentiation.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Nyström, Henrik, 1977, et al.
(författare)
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Platelet-derived growth factor B retention is essential for development of normal structure and function of conduit vessels and capillaries
- 2006
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Ingår i: Cardiovasc Res. - : Oxford University Press (OUP). - 0008-6363. ; 71:3, s. 557-65
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Extracellular retention of PDGF-B has been proposed to play an important role in PDGF-B signalling. We used the PDGF-B retention motif knockout mouse (RetKO) to study the effects of retention motif deletion on development of micro- and macrovascular structure and function. METHODS: Passive and active properties of conduit vessels were studied using myograph techniques and histological examination. Capillary structure and function was studied using measurements of capillary density in skeletal muscle and by assessing aerobic physical performance in a treadmill setup. Cardiac function was assessed using echocardiography. RESULTS: Myograph experiments revealed an increased diameter and stiffness of the aorta in RetKO. Histological examination showed increased media collagen content and a decreased number of aortic wall layers, however with a similar number of vascular smooth muscle cells. This outward eutrophic remodelling of the aorta was accompanied by endothelial dysfunction. RetKO showed decreased capillary density in skeletal muscle and signs of a defective delivery of capillary oxygen to skeletal muscle, as shown by a decreased physical performance. In RetKO mice, echocardiography revealed an adaptive eccentric cardiac hypertrophy. CONCLUSION: We conclude that retention of PDGF-B during development is essential for a normal conduit vessel function in the adult mouse. Furthermore, PDGF-B retention is also necessary for the development of an adequate capillary density, and thereby for a normal oxygen delivery to skeletal muscle. The lack of primary effects on cardiac function supports the redundant role of PDGF-B in cardiac development.
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| 7. |
- Nyström, Henrik, 1977, et al.
(författare)
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Short-term administration of growth hormone (GH) lowers blood pressure by activating eNOS/nitric oxide (NO)-pathway in male hypophysectomized (Hx) rats
- 2005
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Ingår i: BMC Physiol. - : Springer Science and Business Media LLC. - 1472-6793. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the study was to evaluate the acute and continuous (up to 14 days of treatment) effect of growth hormone (GH) on blood pressure (BP) regulation and to investigate the interplay between GH, nitric oxide (NO) and BP. In un-supplemented and GH supplemented hypophysectomized (Hx) male rats as well as intact rats, continuous resting mean arterial blood pressure (MAP) was measured using telemetry. Baroreceptor activity and the influences of NO on BP control were assessed during telemetric measurement. Furthermore, basal plasma and urine nitrate levels and aortic endothelial nitric oxide synthase (eNOS) expression were analysed. Endothelial function as well as vascular structure in the hindquarter vascular bed was estimated using an in vivo constant-flow preparation. RESULTS: Hypophysectomy was associated with decreased MAP (Hx: 83 +/- 3 vs Intact: 98 +/- 6 mmHg, p < 0.05) and heart rate (HR) (Hx: 291 +/- 4 vs Intact: 351 +/- 7 beat/min, p < 0.05). Endothelial dysfunction and reduced vasculature mass in the hindquarter vascular bed was found in Hx rats. GH substitution caused a further transient decrease in MAP and a transient increase in HR (14% and 16% respectively, p < 0.05). The reduction in MAP appeared to be NO dependent. Aortic eNOS expression was unchanged. GH substitution resulted in an impaired baroreceptor function. Two weeks of GH treatment did not normalise the BP, vascular structure and the endothelial function in the resistance vessels. CONCLUSION: GH substitution seems to have a short lasting effect on lowering blood pressure via activation of the NO-system. An interaction between GH, NO-system and BP regulation can be demonstrated.
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| 8. |
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| 9. |
- Robertson, Josefina, et al.
(författare)
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Increased immune activation and signs of neuronal injury in HIV-negative people on preexposure prophylaxis.
- 2021
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Ingår i: AIDS (London, England). - 1473-5571 .- 0269-9370. ; 35:13, s. 2129-2136
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Tidskriftsartikel (refereegranskat)abstract
- Persistent immune activation in the central nervous system and systemically are common in people living with HIV (PLHIV) despite antiretroviral therapy. It is not known whether this is generated by HIV replication or by other components such as coinfections and lifestyle-related factors.The aim of this study was to determine the importance of different factors; it is crucial to find well matched HIV-negative controls. In this context, HIV-negative persons on preexposure prophylaxis (PrEP) may constitute a suitable control group to PLHIV with similar lifestyle-related factors.Cerebrospinal fluid (CSF) and blood were collected from 40 HIV-negative persons on PrEP and 20 controls without PrEP. Biomarkers of immune activation, blood--brain barrier (BBB) integrity and neuronal injury were analysed.CSF and serum β2-microglobulin, serum neopterin and CSF neurofilament light protein were higher in persons on PrEP compared with controls. Furthermore, persons on PrEP had higher CSF/plasma albumin ratio, and matrix metalloproteinase-3 concentrations, indicating BBB dysfunction. Of persons on PrEP, 90% were cytomegalovirus (CMV)-positive compared to 65% of the controls. CMV-positive individuals as a group had higher levels of serum β2-microglobulin than CMV-negative individuals (P<0.05). Drug users had higher serum β2-microglobulin compared to nonusers (P<0.01).HIV-negative persons on PrEP had higher levels of biomarkers for immune activation, BBB impairment and neuronal injury, compared with volunteers without PrEP. Moreover, serum β2-microglobulin was higher in CMV-positive than in CMV-negative individuals and in drug users compared with nonusers. These findings are important to consider when analysing immune activation and CNS injury in PLHIV, and emphasize the importance of appropriate controls.
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| 10. |
- Tivesten, Åsa, 1969, et al.
(författare)
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Cardiac concentric remodelling induced by non-aromatizable (dihydro-)testosterone is antagonized by oestradiol in ovariectomized rats
- 2006
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Ingår i: J Endocrinol. ; 189:3, s. 485-91
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies on the cardiovascular effects of androgens in females, most of them using testosterone treatment, have yielded conflicting results. Testosterone is metabolized into oestradiol (E2) and dihydrotestosterone (DHT) within cardiovascular tissues. The aim of the present study was to explore the cardiovascular effects exerted by E2 and the non-aromatizable androgen DHT and to study possible interactions between these in female rats. Ovariectomized rats were treated with DHT, E2, or DHT+E2 for 6 weeks. DHT increased left-ventricular posterior wall thickness, assessed by echocardiography, whereas left-ventricular dimension, as well as total heart weight and calculated left-ventricular mass, were unchanged. DHT also increased the levels of insulin-like growth factor-I mRNA in the left ventricle. E2 abolished the effect of DHT on left-ventricular remodelling and insulin-like growth factor-I mRNA when the two treatments were given in combination. E2 also reduced androgen receptor mRNA levels in the heart. Neither E2 nor DHT changed blood pressure measured by telemetry. In conclusion, treatment with the endogenous non-aromatizable androgen DHT causes cardiac concentric remodelling in ovariectomized rats, possibly mediated by increased local levels of insulin-like growth factor-I. The effect of DHT on cardiac wall thickness was antagonized by E2, possibly through downregulation of cardiac androgen receptors. These mechanisms may be of importance for the concentric left-ventricular geometric pattern developing in women after menopause.
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