Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice

Objective: The apelin receptor APJ is a putative receptor protein related to angiotensin (Ang) type I receptor. The apelin-APJ system has been implicated in diabetes, but its role in the diabetic vasculature and the mechanisms involved remain unclear. Our aim here was to explore the regulatory role of apelin in the aortic vascular tone in diabetic mice. Methods: A Multi Myograph system was used to determine the isometric vessel tone in aortic rings from diabetic db/db and control db/m+ mice. The mRNA, phosphorylation, and protein levels of APJ, Akt, and endothelial nitric oxide synthase (eNOS) were analyzed by reverse transcription-polymerase chain reaction and Western blotting, respectively. Results: There is depressed expression of APJ, enhanced contractile response to Ang 11, and reduced relaxation response to acetylcholine in aortas from db/db mice. Apelin treatment strikingly reversed the altered aortic vascular responsiveness to Ang 11 and acetylcholine in db/db mice, both of which were abolished by the eNOS inhibitor NG-nitro-L-arginine methyl ester. Finally, in db/db mice, considerable increases in phosphorylation of Akt on serine 473 and of eNOS on serine 1177 were found in aortas pretreated with apelin. Conclusions: Apelin treatment modulates the abnormal aortic vascular tone in response to Ang 11 and acetylcholine by potentiating phosphorylation of Akt and eNOS in diabetic mice, suggesting that the apelin-APJ system might be an important regulator of vascular function in diabetes. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.