title: Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells.
abstract: This study investigated the role of endothelin-1 for hyperglycemia, vascular, and pancreatic injury in early type I diabetes in non-obese-diabetic (NOD) mice. Endothelium dependent relaxation to acetylcholine and vascular gene expression of endothelin converting enzyme (ECE) isoforms 1 and 2 were studied as indicators of vascular injury. Endothelial NO bioactivity in the aorta was reduced in diabetic NOD mice while vascular expression of ECE-1 and ECE-2 mRNA was increased compared with controls (all p<0.05). Vascular histology was normal in all animals. Unexpectedly, treatment of prediabetic NOD mice for 6 weeks with the orally active ET(A) receptor antagonist BSF461314 prevented onset of diabetes without affecting insulitis severity. ET(A) receptor blockade also restored abnormal endothelial NO bioactivity and reduced ECE-1 and ECE-2 gene expression in NOD mice to levels comparable with healthy controls (p<0.05). Moreover, secretion of endothelin-1 in a time-dependent fashion was observed by pancreatic islet beta-cells cultured in vitro. These data suggest a critical role for ET(A) receptor signaling in the development of autoimmune forms of diabetes and the early vascular injury associated with it.
authors: Medical Policlinic, University Hospital Zürich, Switzerland.
authors: Jana
authors: J
authors: Ortmann
authors: Philipp C
authors: PC
authors: Nett
authors: Jennifer
authors: J
authors: Celeiro
authors: Tobias
authors: T
authors: Traupe
authors: Luigi
authors: L
authors: Tornillo
authors: Regina
authors: R
authors: Hofmann-Lehmann
authors: Elvira
authors: E
authors: Haas
authors: Beat
authors: B
authors: Frank
authors: Luigi M
authors: LM
authors: Terraciano
authors: Matthias
authors: M
authors: Barton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice
chemical_list: D019332:Endothelin-1