Published online before print May 5, 2005, doi: 10.1161/01.ATV.0000168896.64927.bb
© 2005 American Heart Association, Inc.
Brief Reviews |
Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase
From II Medizinische Klinik (T.M., A.D., A.M.), Mainz Kardiologie und Angiologie Mainz, Germany; and Fachbereich Biologie (V.U.), Universität Konstanz, Germany.
Correspondence to Thomas Münzel, MD, Professor of Internal Medicine, II Medizinische Klinik und Poliklinik Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany. E-mail tmuenzel{at}uni-mainz.de
Series Editor: Kathy K. Griendling
Redox Mechanisms in Blood Vessels
ATVB in Focus
Previous Brief Reviews in this Series:
•Mueller CFH, Laude K, McNally JS, Harrison DG. Redox mechanisms in blood vessels. 2005;25:274–278.
•Gutterman DD, Miura H, Liu Y. Redox modulation of vascular tone: focus of potassium channel mechanisms of dilation. 2005;25:671–678.
•Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. 2005;25:1102–1111.
•Leopold JA, Loscalzo J. Oxidative enzymopathies and vascular disease. 2005;25:1332–1340.
Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
Key Words: endothelium • vasodilation • nitric oxide • endothelial NO-synthase • oxidative stress
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