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Mol. Cell. Biol. 22 (24): 8467-8477

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Rho GTPase/Rho Kinase Negatively Regulates Endothelial Nitric Oxide Synthase Phosphorylation through the Inhibition of Protein Kinase B/Akt in Human Endothelial Cells

Xiu-Fen Ming,1,2 Hema Viswambharan,1 Christine Barandier,1 Jean Ruffieux,1 Kozo Kaibuchi,3 Sandro Rusconi,2 and Zhihong Yang1*

Vascular Biology, Institute of Physiology,1 Institute of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland,2 Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya, Aichi 466-8500, Japan3

Received for publication 27 February 2002. Accepted for publication 11 September 2002.

Abstract: Endothelial nitric oxide synthase (eNOS) is an important regulator of cardiovascular homeostasis by production of nitric oxide (NO) from vascular endothelial cells. It can be activated by protein kinase B (PKB)/Akt via phosphorylation at Ser-1177. We are interested in the role of Rho GTPase/Rho kinase (ROCK) pathway in regulation of eNOS expression and activation. Using adenovirus-mediated gene transfer in human umbilical vein endothelial cells (HUVECs), we show here that both active RhoA and ROCK not only downregulate eNOS gene expression as reported previously but also inhibit eNOS phosphorylation at Ser-1177 and cellular NO production with concomitant suppression of PKB activation. Moreover, coexpression of a constitutive active form of PKB restores the phosphorylation but not gene expression of eNOS in the presence of active RhoA. Furthermore, we show that thrombin inhibits eNOS phosphorylation, as well as expression via Rho/ROCK pathway. Expression of the active PKB reverses eNOS phosphorylation but has no effect on downregulation of eNOS expression induced by thrombin. Taken together, these data demonstrate that Rho/ROCK pathway negatively regulates eNOS phosphorylation through inhibition of PKB, whereas it downregulates eNOS expression independent of PKB.

* Corresponding author. Mailing address: Vascular Biology, Institute of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland. Phone: 41-26-300-85-93. Fax: 41-26-300-96-36. E-mail: zhihong.yang{at}

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