Defective pancreas vascularisation and downregulation of soluble epoxyde hydrolase gene expression in various organs in Goto-Kakizaki (GK) foetuses

Autor: Giroix, M.H., Irminger, J.C., Calderari, Sophie, Schmidlin, F., Lacraz, Grégory, Cornut, M., Coulaud, J., Kergoat, M., Homo-Delarche, Françoise
Přispěvatelé: Université Paris Diderot - Paris 7 (UPD7), Université de Genève = University of Geneva (UNIGE), Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Merck Serono, Merck & Co. Inc, European Association for the Study of Diabetes (EASD). GBR., Université de Genève (UNIGE), Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), ProdInra, Migration
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Zdroj: 45. Annual Meeting of the European Association for the Study of Diabetes
45. Annual Meeting of the European Association for the Study of Diabetes, Sep 2009, Vienne, Austria. Springer Link, Diabetologia, 52 (S1), 550 p., 2009, 45th EASD Annual Meeting of the European Association for the Study of Diabetes
Popis: International audience; We identified islet inflammation associated with microangiopathy in diabetic GK rats (a spontaneous model of T2D). Signs of islet microangiopathy are also present in prediabetic 1-week-old GK neonates (1-w-GK), together with islet oxidative stress (OS). In addition, GK rats, particularly females, show hypercholesterolemia. Both hyperglycemia and hypercholesterolemia trigger OS and have deleterious effects on vessels. Both also increase placental inflammation, which takes place even during normal pregnancy. Moreover, there is evidence for linking dysmetabolic conditions during pregnancy to hypertension, cardiovascular disease and diabetes in the offspring. This probably occurs via altered foetal programming. Because endothelial signals are essential during islet development, vascular alterations might act during foetal life to trigger T2D. In E21 GK foetuses, β-cell mass is decreased by 80%. Our aims were to evaluate blood glucose and lipids, pancreas vascularisation and gene expression in various organs in E21 GK foetuses, as compared to Wistar controls. glycemia and lipid assays were done on sera; 2) expression of 7 genes, selected on the basis of previous studies conducted in 1-w- Wistar and GK islets, were evaluated by quantitative RT-PCR in umbilical cord, placenta, liver and pancreas; 3) pancreatic vascularisation was quantified after immunohistochemistry for nestin, a recognized endothelial marker. systemic glucose, cholesterol and cholesterol/HDL ratio were significantly higher in GK foetuses, with no difference in triglycerides, FFA and HDL levels; 2) while in 1-w-GK islets, we found a significant upregulation of genes encoding inflammatory molecules, such as caspase-1 (x9.0), IL-18 (x3.9), IL-15 (x1.4) and CXCL-1 (x3.9), the pancreatic expression of the 4 genes was variable from one E21 GK RNA preparation to another, being however more often upregulated. The same trend toward upregulation of inflammatory genes was observed in the placenta, while it was less marked in liver and umbilical cord; the expression of 2 genes encoding proangiogenic factors, neuropilin-1 and neuropeptide Y, which was significantly downregulated in 1-w-GK islets (x0.6 and x0.1, respectively), was not decreased in most E21 GK organs; nevertheless, gene encoding soluble epoxyde hydrolase (sEH), which inhibits the catabolism of epoxyeicosatrienoic acids (EETs), was found to be downregulated by 70-90 % in E21 GK foetal organs; sEH, by increasing levels of EETs, would augment their vasodilatator, antiinflammatory, antioxidative and proangiogenic effects; 3) pancreatic vascularisation was decreased by 60 % in E21 GK foetuses. E21 GK foetuses are hyperglycemic and hypercholesterolemic. Their reduced β-cell mass is associated with decreased pancreatic vasculari sation, which might participate to T2D pathophysiology. The strong underexpression of sEH in various GK foetal organs suggests a very early defence mechanism in GK rats, probably linked to maternal OS induced by carbohydrate and/or lipid disturbances.
Databáze: OpenAIRE
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