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CALL FOR PAPERS
1Medical College of Wisconsin, Biophysics Research Institute, and 2Cardiovascular Center, Milwaukee, Wisconsin 53226
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are now thought to play an important role in the onset of various vascular pathologies. Collectively, ROS refers to free radicals and oxidants derived from one-electron reduction of molecular oxygen. These radicals are the following: superoxide (
), hydrogen peroxide (H2O2), hydroxyl radicals (·OH), lipid peroxyl radical (LOO·), lipid hydroperoxides (LOOH), and aldehydes such as 4-hydroxynonenal (4-HNE), which are formed from the decomposition of LOOH. RNS refers to oxidants formed from nitric oxide (
and peroxynitrite (ONOOH/ONOO–), a potent oxidant formed from the reaction between ·NO and . In addition, chlorinated and brominated oxidants (e.g., HOCl and HOBr) are enzymatically formed from the interaction between chloride-bromide anions and ROS. Recent evidence suggests that extracellular ROS-RNS generate intracellular ROS-RNS through induction of oxidases and stimulation of intracellular signaling pathways. The current thinking is that cells regulate redox-sensitive signal transduction pathways and transcriptional regulatory processes through generation of ROS that act as second messengers.
In this Call for Papers of the American Journal of Physiology-Heart and Circulatory Physiology, we have assembled a variety of investigators with expertise ranging from chemistry of ROS-RNS to their physiological effects in microcirculation. We think this is timely and sincerely hope that the following forum on "Vascular Effects of Free Radicals" will be helpful to researchers in this field.
A review article by Wink and co-workers (12) is included in this collection of papers. They propose the use of nitroxyl (HNO) donors as a novel strategy for treating heart failure (12). HNO is a one-electron reduction intermediate of ·NO. The action of HNO species appears to occur through activation of the neuropeptide calcitonin gene-related peptide that is independent of ·NO-mediated cGMP-dependent mechanism. The authors suggest that ·NO and HNO act through a distinctly different signaling pathway in cardiovascular systems.
Hyperhomocysteinemia is characterized by impaired microvascular endothelial function. Using a rat model of hyperhomocysteinemia, Bagi et al. (1) showed that vitamin C treatment enhanced the bioavailability of ·NO while restoring the associated physiological dilator response to arteriolar wall shear stress. This study provides a therapeutic rationale for using vitamin C in vascular diseases with elevated homocysteine levels (1).
Ceaser et al. (2) describe the role of the mitochondrion on the cellular adaptation to oxidant stress. They report that the exposure of endothelial cells to subtoxic levels of oxidized low-density lipoprotein and to the electrophilic lipid metabolite 4-HNE protects against apoptosis via an increase in mitochondrial complex 1 activity. This study provides an important link between oxidative cell signaling and cellular bioenergetics (2).
In a study by Maas and co-workers (5), the authors demonstrate that exposure of endothelial cells to ROS results in reversible tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa member of the Ig superfamily that exhibits both adhesive and signaling properties. Phosphorylated PECAM-1 can then recruit to the inner face of the plasma membrane the protein Src homology-2-containing protein tyrosine phosphatase, which may become activated via oxidation of a cysteine residue at the active site. It is hypothesized that PECAM-1 may serve as a molecular sensor of oxidative stress during inflammatory processes.
Oltman et al. (9) hypothesize that ROS contribute to arachidonic acid (AA)-induced coronary microvascular dilation. Using isolated porcine coronary microvessels, the authors show that AA-induced vessel relaxation is triggered by cyclooxygenase-catalyzed metabolism of AA. This dilation was inhibited by treatment with indomethacin. Incubation with polyethylene glycol-conjugated superoxide dismutase (SOD) and catalase (PEG-SOD and PEG-catalase) attenuated AA-induced microvessel dilation. The authors conclude that cyclooxygenase-derived ROS may play an important role in the physiological regulation of coronary blood flow (9).
Sato et al. (10) investigated the direct vasomotor effect of exogenously generated ROS. Using human coronary arterioles (HCA), the investigators show that exogenously generated ROS, using xanthine and xanthine oxidase to produce superoxide and H2O2, dilate HCA through different pathways involving the activation of guanylate cyclase and by vascular smooth muscle cell hyperpolarization through an endothelium-derived hyperpolarizing factor (EDHF) mechanism. The vasodilation was the result of generation of H2O2; however, the mechanism of dilation was dependent on whether the H2O2 acted on the cell surface (potassium channel opening) or from within the smooth muscle cell (guanylate cyclase) (10).
In a separate original article, Nozik-Grayck and co-workers (3) discuss a new role for anion exchange proteins in the regulation of pulmonary vascular tone. In this study, the authors show that superoxide anion transport in the pulmonary artery is regulated by bicarbonate anion-chloride ion exchange activity. Thus the extracellular release of superoxide in intact rat lungs and isolated pulmonary artery rings was controlled by bicarbonate levels. The investigators also reported a novel role for endothelial NO synthase in the bicarbonate-dependent release of superoxide in the pulmonary endothelium (3). The results may have clinical implications for subjects with inflammatory causes of alveolar hypoxia.
Thengchaisri and Kuo (11) examined the role of prostaglandin cyclooxygenase-derived metabolites and smooth muscle potassium channel activation in H2O2-mediated coronary arteriolar dilation. Their data suggest that H2O2 induces endothelium-dependent vasodilation through activation of cyclooxygenase-1-dependent prostaglandin E2 formation. The authors conclude that H2O2 is a potent vasodilator of porcine coronary microvessels operating through at least two mechanisms, one endothelium-dependent and the other via a direct effect likely on calcium-activated potassium channels on the underlying vascular smooth muscle (11).
Scott McNally et al. (6) discuss the role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial oscillatory shear stress-induced superoxide production. In this study the authors report that superoxide generation during oscillatory shear stress in endothelial cells lacking the p47phos subunit of NAD(P)H oxidase was vastly decreased. From these results, coupled with those obtained using p47phox-transfected cells and xanthine oxidase inhibitors, the authors provide evidence of a direct link between NADPH oxidase activity and xanthine oxidase levels and that xanthine oxidase is responsible for superoxide formation in endothelial cells subjected to oscillatory shear (6).
Chamseddine and Miller (3) examined the contribution of the gp91phox subunit of NADPH oxidase. They determined the role of this subunit in both vascular adventitial fibroblasts and medial smooth muscle cells using both wild-type and gp91phox-deficient mouse aortas. It was determined that the adventitial fibroblast NAD(P)H oxidase that generates superoxide was dependent on gp91phox, but this was not the case in aortic smooth muscle cells. This may have important implications in the use of genetic models to alter ROS production and in understanding the enzymatic contributions to elevated ROS in specific disease processes.
In this issue, Gupte et al. (4) report on metabolic pathways regulating NAD(P)H homeostasis and the effects on vascular smooth muscle calcium levels and vasomotor tone. Inhibition of the pentose phosphate pathway reduced constrictions mediated by vascular entry of calcium but did not alter responses to agonists that activate PKC. This study identifies a novel metabolic pathway that induces alterations in vascular tone by a redox mechanism involving NAD(P)H and altered calcium entry into the cell.
The role of ROS in regulating vascular function is an emerging area of research. Understanding redox modulation of vasomotor tone will provide new insights into mechanisms of both physiological (e.g. flow-mediated dilation) and pathological conditions such as hyperhomocysteinemia, hypertension, hypercholesterolemia, and other risk factors for coronary disease. By better differentiating the beneficial and detrimental vascular effects of ROS, we can improve therapeutic approaches in conditions such as diabetes, atherosclerosis, and chronic inflammation where excess radical species play an important causative role resulting in intimal proliferation and a hypercoagulable state. Future studies should evaluate the role of EDHF as an agent to improve vascular function because this compound is relatively unaffected by superoxide, which is upregulated in disease conditions (7, 8).
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12,14-PGJ2 increase mitochondrial complex I activity in endothelial cells. Am J Physiol Heart Circ Physiol 285: H2298–H2308, 2003.
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