Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells.
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.
Ortmann
Jana
J
Medical Policlinic, University Hospital Zürich, Switzerland.
Nett
Philipp C
PC
Celeiro
Jennifer
J
Traupe
Tobias
T
Tornillo
Luigi
L
Hofmann-Lehmann
Regina
R
Haas
Elvira
E
Frank
Beat
B
Terraciano
Luigi M
LM
Barton
Matthias
M
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
D019332:Endothelin-1