Insulin-like growth factor binding protein (IGFBP)-3 has both growth-inhibiting and growth-promoting effects at the cellular level. The cytotoxic action of several anticancer drugs is linked to increased ceramide generation through sphingomyelin hydrolysis or de novo biosynthesis. Herein, we investigated the role of IGFBP-3 on apoptosis of human umbilical vein endothelial cells (HUVEC) and its relationship with ceramide levels. We report that IGFBP-3 exerts dual effects on HUVEC, potentiating doxorubicin-induced apoptosis but enhancing survival in serum-starved conditions. Ceramide was increased by IGFBP-3 in the presence of doxorubicin and decreased when IGFBP-3 was added alone to cells cultured in serum-free medium. The protection exerted by the ceramide synthase inhibitor fumonisin B1 over doxorubicin-induced apoptosis was enhanced by IGFBP-3 with concomitant reduction of ceramide levels. IGFBP-3 alone activated sphingosine kinase (SK) and increased SK1 mRNA; the SK inhibitor N,N-dimethylsphingosine (DMS) blocked IGFBP-3 antiapoptotic effect. Moreover, IGFBP-3 increased IGF-I mRNA and dramatically enhanced IGF-I release. IGF-I receptor (IGF-IR) and its downstream signaling pathways Akt and ERK were phosphorylated by IGFBP-3, whereas inhibition of IGF-IR phosphorylation with tyrphostin AG1024 suppressed the antiapopoptic effect of IGFBP-3. Finally, IGFBP-3 increased endothelial cell motility in all experimental conditions. These findings provide evidence that IGFBP-3 differentially regulates endothelial cell apoptosis by involvement of the sphingolipid signaling pathways. Moreover, the survival effect of IGFBP-3 seems to be mediated by the IGF-IR.
SignificancePathological cardiac hypertrophy, characterized by heart growth in response to pressure or volume overload, such as in the setting of hypertension, is the main risk factor for heart failure (HF). The identification of therapeutic strategies to prevent or reverse cardiac hypertrophy is therefore a priority for curing HF. It is known that growth hormone-releasing hormone (GHRH) displays cardioprotective functions; however, its therapeutic potential in hypertrophy and HF is unknown. Here we show that GHRH reduces cardiomyocyte hypertrophy in vitro through inhibition of hypertrophic pathways. In vivo, the GHRH analog MR-409 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction and improves cardiac function. These findings suggest therapeutic use of GHRH analogs for treatment of pathological cardiac hypertrophy and HF.
Availability of large amounts of in vitro generated β-cells may support replacement therapy in diabetes. However, methods to obtain β-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic β-cell survival and function. Obestatin prevents β-cell apoptosis, preserves β-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro β-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i) enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii) increased cell survival and reduced apoptosis during precursor selection; (iii) promoted the generation of islet-like cell clusters (ICCs) with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs), Notch receptors and neurogenin 3 (Ngn3) during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional β-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration.
Availability of large amounts of in vitro generated b-cells may support replacement therapy in diabetes. However, methods to obtain b-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic b-cell survival and function. Obestatin prevents b-cell apoptosis, preserves b-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro b-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i) enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii) increased cell survival and reduced apoptosis during precursor selection; (iii) promoted the generation of islet-like cell clusters (ICCs) with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs), Notch receptors and neurogenin 3 (Ngn3) during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional b-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration.
The purpose of this study was to assess the sensitivity of 5-HT1D receptors in migraine using sumatriptan as a pharmacological probe. The drug stimulates the release of growth hormone (GH) and this effect may be used to explore the function of cerebral serotonergic systems in vivo. We administered sumatriptan and placebo to 15 migraineurs and to 10 controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injection. Placebo had no effect on hormone concentrations. Sumatriptan induced a significant (P<0.01) increase in GH concentrations both in migraine patients and healthy controls. The GH increase was not significantly different in the two groups. Our results suggest that cerebral serotonergic functions mediated by 5-HT1D receptors are not altered in migraine. Sumatriptan overuse could lead to adverse effects mediated by its neuroendocrine activity.
OBJECTIVE:The reduction of spontaneous and stimulated growth hormone (GH) secretion in obesity could reflect an increase of the inhibitory effect of insulin growth factor I (IGF-I) on somatotroph secretion. DESIGN: In the present study we aimed to verify the effect of low dose recombinant human IGF-I (20 mg=kg subcutaneously (s.c.) at 0 min) on 3 h-spontaneous GH secretion (mGHc, 0 -180 min) and on the GH response to growth hormone releasing hormone (GHRH) (1 mg=kg i.v. at þ 180 min) in obesity. SUBJECTS: Five obese women with abdominal adiposity (OB, age, mean AE s.e.m.: 31 AE 7.13 y; BMI: 32.04 AE 3.69 kg=m 2 ) and eight age-matched lean women (NW, 28.3 AE 1.2 y; 20.1 AE 0.5 kg=m 2 ) were studied. RESULTS: The mGHc and GHRH-induced GH response in OB (1.0 AE 0.7 mg=l; AUC 180 -270 min : 688.6 AE 202.4 mg=l min, respectively) were lower than in NW (2.6 AE 0.8 mg=l, 1315.9 AE 189.9 mg=l min, respectively, P < 0.05). The administration of rhIGF-I increased circulating IGF-I levels in OB and NW to the same extent (339.0 AE 50.39 and 420.3 AE 30.5 mg=l, respectively). The rhIGF-I administration did not affect mGHc in OB or NW (1.1 AE 0.9 and 3.2 AE 1.0 mg=l, respectively) but inhibited (P < 0.05) the GH response to GHRH in OB (324.2 AE 153.1 mg=l) and NW (730.2 AE 288.1 mg=l). CONCLUSIONS: Our study shows that the administration of low dose rhIGF-I reduces the somatotroph responsiveness to GHRH in obesity as well as in normal subjects.
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