on October 25, 2004
Published online before print October 25, 2004, doi: 10.1161/01.HYP.0000147559.10261.a7
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 10, 2004
From the Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan. * To whom correspondence should be addressed. E-mail: kamata{at}hoshi.ac.jp.
Abstract--The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NOx- (NO2-+NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110
Revised on June 28, 2004
Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model
Tsuneo Kobayashi;
subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes.
Key words: diabetes mellitus • hyperinsulinism • aorta • endothelium-derived relaxing factor • nitric oxide
This article has been cited by other articles:
 |
|
 |
|
  T. Kobayashi, K. Taguchi, S. Nemoto, T. Nogami, T. Matsumoto, and K. Kamata Activation of the PDK-1/Akt/eNOS pathway involved in aortic endothelial function differs between hyperinsulinemic and insulin-deficient diabetic rats Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1767 - H1775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, J. Zhang, Z. Ungvari, and C. Zhang Resveratrol Improves Endothelial Function: Role of TNF{alpha} and Vascular Oxidative Stress Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1164 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, K. Ishida, N. Nakayama, T. Kobayashi, and K. Kamata Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1388 - H1397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-S. Zhou, I. H. Schulman, and L. Raij Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H833 - H839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, E. Noguchi, K. Ishida, T. Kobayashi, N. Yamada, and K. Kamata Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1165 - H1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, M. Kakami, E. Noguchi, T. Kobayashi, and K. Kamata Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of Type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1480 - H1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. H. Schulman, M.-S. Zhou, E. A. Jaimes, and L. Raij Dissociation between metabolic and vascular insulin resistance in aging Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H853 - H859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Potenza, F. L. Marasciulo, M. Tarquinio, M. J. Quon, and M. Montagnani Treatment of Spontaneously Hypertensive Rats With Rosiglitazone and/or Enalapril Restores Balance Between Vasodilator and Vasoconstrictor Actions of Insulin With Simultaneous Improvement in Hypertension and Insulin Resistance Diabetes, December 1, 2006; 55(12): 3594 - 3603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kobayashi, Y. Hayashi, K. Taguchi, T. Matsumoto, and K. Kamata ANG II enhances contractile responses via PI3-kinase p110{delta} pathway in aortas from diabetic rats with systemic hyperinsulinemia Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H846 - H853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, T. Kobayashi, K. Wakabayashi, and K. Kamata Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1933 - H1940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kobayashi, T. Matsumoto, and K. Kamata IGF-I-induced enhancement of contractile response in organ-cultured aortae from diabetic rats is mediated by sustained thromboxane A2 release from endothelial cells J. Endocrinol., August 1, 2005; 186(2): 367 - 376. [Abstract] [Full Text] [PDF]
|
|