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Åsa Tivesten, Anna Barlind, Kenneth Caidahl, Natalia Klintland, Antonio Cittadini, Claes Ohlsson and Jörgen Isgaard

Growth hormone (GH) deficiency is associated with abnormal vascular reactivity and development of atherosclerosis. GH treatment in GH deficient states restores systemic vascular resistance, arterial compliance, endothelium-dependent and endothelium-independent vasodilation, and may reverse markers of early atherosclerosis. However, very little is known about the molecular mechanisms underlying these effects. In the present study, male Sprague Dawley rats were hypophysectomized and treated for two weeks with GH (recombinant human GH, 2 mg/kg/day) or saline as s.c. injections twice daily. GH decreased aortic systolic blood pressure compared with saline-treated animals, while the diastolic blood pressure was not significantly changed. GH treatment increased cardiac output as determined by Doppler-echocardiography and the calculated systemic vascular resistance was markedly reduced. In order to identify GH-regulated genes of importance for vascular function, aortic mRNA levels were analyzed by the microarray technique and correlated to the systolic blood pressure levels. Using this approach, we identified 18 GH-regulated genes with possible impact on vascular tone and atherogenesis. In particular, mRNA levels of the inwardly rectifying potassium channel Kir6.1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both up-regulated by GH treatment and highly correlated to systolic blood pressure. Our findings establish a major role for GH in the regulation of vascular physiology and gene expression. Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone.

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Johan Svensson, Åsa Tivesten, Klara Sjögren, Olle Isaksson, Göran Bergström, Subburaman Mohan, Johan Mölne, Jörgen Isgaard and Claes Ohlsson

The GH/-IGF-I axis is important for kidney size and function and may also be involved in the development of renal failure. In this study, the role of liver-derived endocrine IGF-I for kidney size and function was investigated in mice with adult liver-specific IGF-I inactivation (LI-IGF-I−/− mice). These mice have an 80–85% reduction of serum IGF-I level and compensatory increased GH secretion. Seven-month-old as well as 24-month-old LI-IGF-I−/− mice had decreased kidney weight. Glomerular filtration rate, assessed using creatinine clearance as well as creatinine clearance corrected for body weight, was unchanged. The 24-h urine excretion of sodium and potassium was increased in the LI-IGF-I−/− mice. In the 24-month-old mice, there was no between-group difference in kidney morphology. Microarray and real-time PCR (RT-PCR) analyses showed a high renal expression of IGF-II in the control mice, whereas in the LI-IGF-I−/− mice, there was a tissue-specific decrease in the renal IGF-II mRNA levels (−79%, P < 0.001 vs controls using RT-PCR). In conclusion, deficiency of circulating liver-derived IGF-I in mice results, despite an increase in GH secretion, in a global symmetrical decrease in kidney size, increased urinary sodium and potassium excretion, and a clear down regulation of renal IGF-II expression. However, the LI-IGF-I−/− mice did not develop kidney failure or nephrosclerosis. One may speculate that liver-derived endocrine IGF-I induces renal IGF-II expression, resulting in symmetrical renal growth.

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Marion Walser, Linus Schiöler, Jan Oscarsson, Maria A I Åberg, Ruth Wickelgren, Johan Svensson, Jörgen Isgaard and N David Åberg

The endogenous secretion of growth hormone (GH) is sexually dimorphic in rats with females having a more even and males a more pulsatile secretion and low trough levels. The mode of GH administration, mimicking the sexually dimorphic secretion, has different systemic effects. In the brains of male rats, we have previously found that the mode of GH administration differently affects neuron–haemoglobin beta (Hbb) expression whereas effects on other transcripts were moderate. The different modes of GH administration could have different effects on brain transcripts in female rats. Hypophysectomised female rats were given GH either as injections twice daily or as continuous infusion and GH-responsive transcripts were assessed by quantitative reverse transcription polymerase chain reaction in the hippocampus and parietal cortex (cortex). The different modes of GH-administration markedly increased Hbb and 5′-aminolevulinate synthase 2 (Alas2) in both brain regions. As other effects were relatively moderate, a mixed model analysis (MMA) was used to investigate general effects of the treatments. In the hippocampus, MMA showed that GH-infusion suppressed glia- and neuron-related transcript expression levels, whereas GH-injections increased expression levels. In the cortex, GH-infusion instead increased neuron-related transcripts, whereas GH-injections had no significant effect. Interestingly, this contrasts to previous results obtained from male rat cortex where GH-infusion generally decreased expression levels. In conclusion, the results indicate that there is a small but significant difference in response to mode of GH administration in the hippocampus as compared to the cortex. For both modes of GH administration, there was a robust effect on Hbb and Alas2.

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Marion Walser, Linus Schiöler, Jan Oscarsson, Maria A I Åberg, Johan Svensson, N David Åberg and Jörgen Isgaard

The endogenous secretion pattern in males of GH is episodic in rats and in humans, whereas GH administration is usually even. Different types of GH administration have different effects on body mass, longitudinal bone growth, and liver metabolism in rodents, whereas possible effects on brain plasticity have not been investigated. In this study, GH was administered as a continuous infusion or as two daily injections in hypophysectomized male rats. Thirteen transcripts previously known to respond to GH in the hippocampus and parietal cortex (cortex) were assessed by RT-PCR. To investigate the effects of type of GH administration on several transcripts with different variations, and categories of transcripts (neuron-, glia-, and GH-related), a mixed model analysis was applied. Accordingly, GH injections increased overall transcript abundance more than GH infusions (21% in the hippocampus, P<0.001 and 10% in the cortex, P=0.09). Specifically, GH infusions and injections robustly increased neuronal hemoglobin beta (Hbb) expression significantly (1.8- to 3.6-fold), and GH injections were more effective than GH infusions in increasing Hbb in the cortex (41%, P=0.02), whereas a 23% difference in the hippocampus was not significant. Also cortical connexin 43 was higher in the group with GH injections than in those with GH infusions (26%, P<0.007). Also, there were differences between GH injections and infusions in GH-related transcripts of the cortex (23%, P=0.04) and glia-related transcripts of the hippocampus (15%, P=0.02). Thus, with the exception of Hbb there is a moderate difference in responsiveness to different modes of GH administration.

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Marion Walser, Maria Teresa Samà, Ruth Wickelgren, Maria Åberg, Mohammad Bohlooly-Y, Bob Olsson, Jan Törnell, Jörgen Isgaard and N David Åberg

GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2′-deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increased Igf1 and Gfap mRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a (Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2 (Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs (Glul)). However, IGF1R was correlated with the expression of Dor, Nr2a, Sapap2, Gs and Gfap. In summary, although local bGH expression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose–response curve and cell-specific expression of bGH.

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N David Åberg, Inger Johansson, Maria A I Åberg, Johan Lind, Ulf E Johansson, Christiana M Cooper-Kuhn, H Georg Kuhn and Jörgen Isgaard

IGF-I treatment has been shown to enhance cell genesis in the brains of adult GH- and IGF-I-deficient rodents; however, the influence of GH therapy remains poorly understood. The present study investigated the effects of peripheral recombinant bovine GH (bGH) on cellular proliferation and survival in the neurogenic regions (subventricular zone (SVZ), and dentate gyrus of the hippocampus), as well as the corpus callosum, striatum, parietal cortex, and piriform cortex. Hypopituitarism was induced in female rats by hypophysectomy, and the rats were supplemented with thyroxine and cortisone acetate. Subsequently, the rats received daily s.c. injections of bGH for either 6 or 28 days respectively. Following 5 days of peripheral bGH administration, the number of bromodeoxyuridine (BrdU)-positive cells was increased in the hippocampus, striatum, parietal cortex, and piriform cortex after 6 and 28 days. In the SVZ, however, BrdU-positive cells increased only after 28 days of bGH treatment. No significant change was observed in the corpus callosum. In the hippocampus, after 28 days of bGH treatment, the number of BrdU/NeuN-positive cells was increased proportionally to increase the number of BrdU-positive cells. 3H-thymidine incorporation in vitro revealed that 24 h of bGH exposure was sufficient to increase cell proliferation in adult hippocampal progenitor cells. This study shows for the first time that 1) peripheral bGH treatment increased the number of newborn cells in the adult brain and 2) bGH exerted a direct proliferative effect on neuronal progenitor cells in vitro.