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(Hypertension. 2009;54:744.)
© 2009 American Heart Association, Inc.

Original Articles

Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C

Potential Clinical Implications in Hypertension

Ana Fortuño; Julen Bidegain; Pablo A. Robador; José Hermida; Jacinto López-Sagaseta; Oscar Beloqui; Javier Díez; Guillermo Zalba

From the Division of Cardiovascular Sciences, Centre for Applied Medical Research (A.F., J.B., P.A.R., J.H., J.L.-S., J.D., G.Z.) and Departments of Internal Medicine (O.B.) and Cardiology and Cardiovascular Surgery (J.D.), University Hospital, University of Navarra, Pamplona, Spain.

Correspondence to Ana Fortuño, Center for Applied Medical Research, Pio XII 55, 31008 Pamplona, Spain. E-mail afortuno{at}unav.es

Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate–induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate–stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate–stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients.

Key Words: EXP3179 • hypertension • losartan • metalloproteinases • NADPH oxidase • PKC

Related Article:

Protein Kinase C-Inhibiting Properties of the Losartan Metabolite EXP3179 Make the Difference

Philip Wenzel, Eberhard Schulz, and Thomas Münzel
Hypertension 2009 54: 707-709. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				P. Wenzel, E. Schulz, and T. Munzel Protein Kinase C-Inhibiting Properties of the Losartan Metabolite EXP3179 Make the Difference Hypertension, October 1, 2009; 54(4): 707 - 709. [Full Text] [PDF]