(Circulation. 2000;101:676.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Regulation of Endothelial Constitutive Nitric Oxide Synthase Gene Expression in Endothelial Cells and In Vivo
A Specific Vascular Action of Insulin
From the Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, Mass.
Correspondence to George L. King, MD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail kingg{at}joslab.harvard.edu
Background—The vasodilatory effect of insulin can be acute or increase with time from 1 to 7 hours, suggesting that insulin may enhance the expression of endothelial nitric oxide synthase (eNOS) in endothelial cells. The objective of the present study was to characterize the extent and signaling pathways by which insulin regulates the expression of eNOS in endothelial cells and vascular tissues.
Methods and Results—Physiological concentrations of insulin (10-10 to 10-7 mmol/L) increased the levels of eNOS mRNA, protein, and activity by 2-fold after 2 to 8 hours of incubation in cultured bovine aortic endothelial cells. Insulin enhanced eNOS gene expression in microvessels isolated from Zucker lean rats but not from insulin-resistant Zucker fatty rats. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase) decreased the effect of insulin on eNOS gene expression, but a general protein kinase C (PKC) inhibitor, GF109203X or PKCß isoform inhibitor, LY333531 enhanced eNOS expression. In contrast, PKC activators inhibited both the activation by insulin of PI-3 kinase and eNOS mRNA levels. Overexpression of PKCß isoform in endothelial cells inhibited the stimulation by insulin of eNOS expression and PI-3 kinase activities in parallel.
Conclusions—Insulin can regulate the expression of eNOS gene, mediated by the activation of PI-3 kinase, in endothelial cells and microvessels. Thus, insulin may chronically modulate vascular tone. The activation of PKC in the vascular tissues as in insulin resistance and diabetes may inhibit PI-3 kinase activity and eNOS expression and may lead to endothelial dysfunctions in these pathological states.
Key Words: insulin • nitric oxide • RNA • endothelium • cells • diabetes mellitus • proteins
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K. Suzuma, K. Naruse, I. Suzuma, N. Takahara, K. Ueki, L. P. Aiello, and G. L. King Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR, Flt1, and Phosphatidylinositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells J. Biol. Chem., December 22, 2000; 275(52): 40725 - 40731. [Abstract] [Full Text] [PDF]
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M. Montagnani, I. Golovchenko, I. Kim, G. Y. Koh, M. L. Goalstone, A. N. Mundhekar, M. Johansen, D. F. Kucik, M. J. Quon, and B. Draznin Inhibition of Phosphatidylinositol 3-Kinase Enhances Mitogenic Actions of Insulin in Endothelial Cells J. Biol. Chem., January 11, 2002; 277(3): 1794 - 1799. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, and M. A. Creager Inhibition of Protein Kinase C{beta} Prevents Impaired Endothelium-Dependent Vasodilation Caused by Hyperglycemia in Humans Circ. Res., January 11, 2002; 90(1): 107 - 111. [Abstract] [Full Text] [PDF]
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