Circulating isoprostanes: gate keepers in the route from oxidative stress to vascular dysfunction.

Through reading textbooks on pathophysiology, medical students already learn during their early university years that cardiovascular disease (CVD) is closely associated with oxidative stress, which apparently promotes progression of diseases like atherosclerosis, diabetes mellitus, hypertension, and ischemic heart disease. Oxidative stress is created through reactive oxygen species (ROS), eg, the superoxide anion and hydrogen peroxide, that are generated mainly within the mitochondrial respiratory chain or through activity of NADPH oxidases and reduce the bioavailability of nitric oxide (NO), which is the nodal point of endothelial vasomotor control and vascular function.1 ROS are not only prooxidative reactive substances that alter the bioactivity of a variety of cellular molecules but are also known to regulate several classes of genes that are involved in the complex network of vascular growth and function, eg, formation of focal adhesion molecules, expression of metalloproteinases, cytokines and growth factors and, thus, when occurring in excessive amounts, may tilt the endothelial balance toward vasoconstriction and endothelial dysfunction. Furthermore, ROS can interfere with the plasma membrane phospholipid bilayer, which is easily prone to lipid peroxidation, thus resulting in the generation of a number of degradation products displaying potential detrimental bioactivity that may finally initiate vascular dysfunction. Over the last decade, a number of biomarkers of oxidative stress in vivo have been identified that caution against cardiovascular risk factors, the severity of CVD, and cardiovascular outcomes. Among these biomarkers of oxidative stress are a class of prostaglandin F2–like compounds (F2-isoprostanes [F2-IsoPs]), which are generated from the nonenzymatic, free radical–catalyzed peroxidation of phospholipid-bound arachidonic acid independently of the cyclooxygenase pathway. Until recently, IsoPs were considered just as 1 class of oxidative stress markers of CVD among others because they were found to be elevated under conditions of ischemia/reperfusion and atherosclerosis but also in plasma and urine of patients at high cardiovascular risk, such as smokers and hypercholesterolemic, diabetic, and obese patients.2 However, a closer inspection of the biological functions of IsoPs revealed that they indeed activate specific signaling pathways that may be crucial for the pathogenesis of a large variety of diseases, not only related to heart and vascular function but also to neurodegenerative disorders like Alzheimer’s or Parkinson’s disease,3 which are well known to be associated with dysregulated ROS production. IsoPs were first discovered by Morrow and colleagues4,5 and were detected in all biological tissues and fluids, including plasma, urine, bronchoalveolar lavage fluid, cerebrospinal fluid, and bile. Chemically, 3 arachidonyl radicals give rise to 4 F2-IsoP regioisomers, each of which comprises 8 racemic diastereomers.6 Because they are relatively stable as compared to lipoperoxides and aldehydes, they can be easily detected in body fluids and are currently considered as the most reliable markers of lipid peroxidation as recently evaluated by a multilaboratory study of the National Institute of Environmental Health Sciences.7 More recently, it became apparent that IsoPs exhibit significant bioactivity and (besides their feature to serve as an easy to handle oxidative stress biomarker) play a role in the pathogenesis of CVD associated with oxidant injury. Namely, IsoPs were shown to contribute to the progression of atherosclerosis, to interact with platelets by either stimulatory or inhibitory pathways8 and to act as powerful vasoconstrictors, thus inducing hypertension, enhancing ischemia, and potentially initiating a vicious cycle of ROS generation. However, although some hints pointed toward adverse vascular effects of IsoPs, the final proof of their involvement in inhibition of angiogenesis and vascular damage so far had been missing. This gap is filled by Benndorf et al in this issue of Circulation Research.9 The authors elegantly demonstrate that IsoPs exert antiangiogenic effects by interfering with vascular endothelial growth factor (VEGF) signaling pathways, the classic signaling cascade widely involved in various aspects of angiogenesis, vascular homeostasis, and vascular remodeling. Using in vitro and in vivo models of angiogenesis, ie, human coronary artery endothelial cells (HCAECs), the in vitro cardiac angiogenesis assay, as well as the in vivo chorioallantois membrane model of vasculogenesis, the authors conclusively demonstrated that different IsoPs inhibited not only VEGF-mediated endothelial cell migration but also vascular tube formation. Moreover, the authors succeeded in identifying previously unknown biologically active decomposition products of specific IsoPs, namely the cyclopentenone isoprostane derivatives X and Y, which may exert antiangiogenic effects in vivo, contribute to the progression of CVD, and may be exploited as further reliable biomarkers of CVD in the near future. The findings of Benndorf et al are challenging with regard to the welldescribed role of the VEGF family and its receptor system as The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology (H.S.), Justus Liebig University Giessen; and Department of Internal Medicine I (M.W.), Cardiology Division, Friedrich Schiller University Jena, Germany. Correspondence to Prof Dr Heinrich Sauer, Department of Physiology, Justus Liebig University Giessen, Aulweg 129, 35392 Giessen, Germany. E-mail [email protected] (Circ Res. 2008;103:907-909.) © 2008 American Heart Association, Inc.