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Cardiovascular Research 2006 71(2):191-194; doi:10.1016/j.cardiores.2006.05.018
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Copyright © 2006, European Society of Cardiology

Transmitting biological information using oxygen: Reactive oxygen species as signalling molecules in cardiovascular pathophysiology

Ajay M. Shaha,* and Heinrich Sauerb,1

aDepartment of Cardiology, King's College London School of Medicine, Bessemer Road, London SE5 9PJ, UK
bDepartment of Physiology, University of Giessen, Aulweg 129, 35392 Giessen, Germany

* Corresponding author. Tel.: +44 207 346 3865; fax: +44 207 346 4771. Email address: ajay.shah{at}kcl.ac.uk heinrich.sauer{at}physiologie.med.uni-giessen.de

Received 17 May 2006; accepted 22 May 2006

The involvement of reactive oxygen species (ROS) in deleterious processes such as DNA damage and reperfusion injury has long been recognized. More recently, however, it has been appreciated that ROS can specifically modulate diverse intracellular signalling pathways through covalent modifications of target molecules ("redox signalling"), thereby inducing distinct changes in cell phenotype that are important in many physiological and pathophysiological processes [1]. Indeed, some ROS such as H2O2 may be ideally suited to serve as signalling molecules in that they are small, highly diffusible, and rapidly generated and degraded. Despite an exponentially growing amount of information on the sources and mechanisms of ROS generation as well as their degradation by the antioxidant defence system, we are just starting to learn how ROS signalling may function within cells and in a coordinated way within tissues and organs.

The numerous sources of ROS generation, which include the mitochondrial respiratory chain and enzymes such as the NADPH oxidases (Noxs), xanthine oxidase, uncoupled nitric oxide (NO) synthases, 5-lipooxygenase, and cyclooxygenases, are counterbalanced by a large number of endogenous antioxidants and antioxidant enzymes. This raises the question of how individual ROS could specifically govern diverse signalling events and thereby regulate, in the cardiovascular system, physiological processes such as endothelial migration, vascular smooth muscle proliferation, and angiogenesis, as well as initiate pathophysiological modifications of tissue and organs, resulting in atherosclerosis, hypertension, cardiac hypertrophy, and cardiac and vascular remodelling. One possible answer could be the cell type-specific and subcellular localization of ROS sources and sinks which may allow spatial targeting of ROS to protein adaptor molecules which, after redox modification and subsequent structural change, could then further transmit the redox signal downstream. Indeed, distinct subcellular localization of Nox isoforms has recently been suggested to occur in vascular smooth muscle cells with differential compartmentalization in specific signalling domains in the membrane and focal adhesions [2]. Another view could be that concentration gradients of antioxidant molecules exist in cells and tissues that regulate a distinct flow of ROS by forming spatially distinct "broad highways" and "narrow alleys" of ROS fluxes towards specific targets of high versus low redox sensitivity. Gradients in intracellular pH and oxygen concentration might also be transduced into site-specific ROS generation; e.g., ROS generation beneath plasma membranes could be facilitated by low, submembranous pH levels [3] or – rather paradoxically – gradients of hypoxia could be transformed at sites of pronounced ROS generation [4–6].

A significant problem in the efforts to understand the complexities of ROS signalling is the lack of appropriate tools to identify specific ROS within cells at sufficiently high spatial and temporal resolution in order to investigate these possibilities. Nevertheless, substantial progress has been made in recent years in understanding the complexity of ROS-mediated signal transduction, its regulation, and functional significance. It is therefore timely to compile this Spotlight Issue, which covers many topical aspects of the field. We appreciate that ROS have many other important effects, for example their involvement in the inactivation of NO and the genesis of endothelial dysfunction, but have focussed primarily on redox signalling in this issue.

A perennial question in the context of redox signalling is to understand what may be the evolutionary advantages of ROS production and their use to transmit biological information. The article by Acker et al. [7] provides at least one answer to this conundrum by illustrating the involvement of ROS in oxygen sensing, a process that is essential in the development and healthy existence of aerobic organisms and which is centrally important in cardiovascular homeostasis. These authors clearly show that oxygen-sensitive production of ROS, perhaps from several different ROS-generating sources, may modulate a diverse range of adaptive cascades in which the transcription factor HIF1{alpha} has a central role. Methodology for the highly sensitive and specific detection of ROS is an important requirement in the field, but remains a major challenge. Acker et al. [7] discuss approaches to improving the spatial resolution of ROS localization in cells, while in an original paper by Biondi et al. [8], a new method for detecting hydroxyl radicals in intact organs is presented that uses hydroxylation of D-phenylalanine by hydroxyl radicals followed by HPLC analysis. With this novel technology, the authors were able to detect hydroxytyrosine isomers down to the fmol level, which represents a hitherto unachieved sensitivity of ROS detection.

In order for ROS to be involved in signal transduction, it is self-evident that the process needs to be specific and tightly regulated. A seminal advance in recent years has been the discovery that a family of highly specialized enzymes, the NADPH oxidases, are especially well suited for a central role in redox signalling as a consequence of their specific upstream ligand-dependent activation and their coupling to distinct downstream redox-sensitive targets [9]. Geiszt [10] provides a comprehensive review of current knowledge regarding the molecular structure, biochemical properties, and regulation of the six members of the Nox family of NADPH oxidases that have been identified to date. Clempus and Griendling [11] cover redox signalling in the vascular smooth muscle cell, focussing on the involvement of NADPH oxidases, their activation, and the orchestration of downstream cascades – an area in which this group has made seminal contributions. Ushio-Fukai [12] focuses on the endothelial cell and detailed studies on the ROS-dependent mechanisms involved in angiogenesis. These articles also present aspects of a developing paradigm for the spatial targeting of ROS production and subsequent activation of distinct redox-sensitive kinases in which a key aspect is protein–protein interactions involving NADPH oxidase components and other signalling molecules. These review articles also illustrate the utility of state-of-the-art molecular approaches in defining the involvement of individual Nox isoforms in specific settings – especially important given the lack of suitable pharmacological probes with sufficient specificity. The paper by ten Freyhaus et al. [13] describes the use of a novel Nox inhibitor, VAS2870, to discriminate the NADPH oxidase contribution versus NO synthase-mediated biological effects in PDGF-dependent smooth muscle chemotaxis, but good Nox isoform-specific inhibitors are still required.

Redox signalling in the endothelial cell is also the topic of the article by Moldovan and colleagues [14] who focus on regulation of the actin cytoskeleton and cell motility and the roles of the small GTPase Rac1, which exerts at least a significant component of its effects through the activation of NADPH oxidase. The precise mechanisms underlying the regulation of NADPH oxidase activity by Rac1 are important to define. An original article by Custodis et al. [15] in this issue investigates this in the context of angiotensin II- or aortic constriction-induced cardiac hypertrophy and demonstrates an important role for phosphatidylinositol 3-kinase (PI3-kinase)-dependent association of Rho guanine nucleotide dissociation inhibitor (RhoGDI{alpha}) to Rac1. In another study, Wenzel et al. [16] convincingly demonstrate that different PI3-kinase isoforms have distinct effects on different ROS-dependent signalling pathways in cardiomyocytes, with p110β regulating the angiotensin II pathway and p110{alpha} being involved in {alpha}-adrenergic-induced signalling.

The vascular theme is extended by Paravicini and Touyz [17], who consider the involvement of ROS in the pathophysiology of different types of hypertension, acting through several mechanisms including direct actions on the vascular smooth muscle, induction of endothelial dysfunction, and central effects. In an original paper, Gao et al. [18] show that ROS released from perivascular adipose tissue in response to perivascular nerve stimulation may act on smooth muscle and endothelial cells to enhance the arterial contractile response. These findings suggest a hitherto neglected but possibly important role of vascular adipose tissue in the regulation of vascular tone. In atherosclerosis, ROS may exert pathophysiological effects not only through redox signalling but also by inducing DNA damage. Mahmoudi et al. [19] discuss the relevance of this, focusing particularly on the sensing and repair mechanisms employed by cells to deal with this insult.

Lehoux [20] addresses the induction of ROS generation by mechanical stimuli and the involvement of redox signalling in vascular remodelling responses to shear and stretch. These mechanisms are potentially relevant to many vascular diseases where haemodynamic alterations are a factor. There are some parallels in the redox signalling involved in cardiac remodelling, which is addressed by two separate articles. Sen et al. [21] review the oxygen-sensitive mechanisms involved in remodelling following cardiac ischaemia–reperfusion with specific focus on the role of perceived hyperoxia; that is, a reoxygenation-associated relative elevation of local pO2 in the context of a reduced normoxia setpoint. Signalling initiated in response to perceived hyperoxia, which involves ROS, appears to play a role in myocardial healing following MI. Murdoch et al. [22] discuss recent data implicating NADPH oxidase-derived ROS as critical mediators of cardiac fibrosis and remodelling in the context of increased RAAS activation as well as during chronic pressure overload and following MI. NADPH oxidases orchestrate a series of changes in phenotype, including increased NF-{kappa}B translocation, matrix metalloproteinase activation, and altered expression of matrix proteins, as well as having effects on myocardial contractile function. These data explain at least some of the effects of increased oxidative stress associated with chronic heart failure (CHF).

Oxidative stress in CHF is also the subject of the article by Sun et al. [23] whose focus is systemic mechanisms implicated in the genesis of oxidative stress, in particular aldosteronism and secondary hyperparathyroidism, which lead to altered cation balance. The authors suggest that this could, in part, be addressed by attention to the balance of dietary micro- and macronutrients. The redox regulation of cardiac excitation–contractile coupling is addressed in detail by Zima and Blatter [24]. Modification of sulfhydryl groups of cysteine residues on the sarcoplasmic reticulum (SR) Ca2+ release channel (or ryanodine receptor, RyR), the SR Ca2+ ATPase, and the L-type channel are involved in altering the function of these proteins and thus myocyte Ca2+ regulation. While the involvement of such effects in reperfusion injury is clear, more recent data suggest that such modifications may also be involved in more subtle physiological regulation of excitation–contraction coupling. Indeed, the data of Heinzel et al. [25] presented in this Spotlight show that formation of ROS occurs when contraction frequency is increased in rat cardiomyocytes – raising the interesting and important question of how the production and effects of ROS are linked to cardiac contractile function.

Collectively, the review articles and original papers in this issue highlight some of the directions in which progress has been made in understanding the basic biology and pathophysiology of the involvement of ROS as signalling molecules in cardiovascular diseases. However, it is notable that such understanding has not been matched thus far by the development of appropriate therapeutic strategies for these conditions. Indeed, antioxidant strategies have been singularly unsuccessful to date in clinical trials [26,27]. Perusal of the collection of articles herein should make it perfectly evident that the involvement of ROS in disease pathophysiology is considerably more complex than a simple "deleterious" effect that could be targeted by global "antioxidants". Instead, it may be necessary to target discrete redox-sensitive pathways in a cell-, tissue-, and disease stage-specific manner. Indeed, several existing drugs may exert some of their effects through such mechanisms (e.g. statins, ACE inhibitors, and angiotensin receptor blockers). A better understanding of the complexities of redox signalling and its regulation may eventually allow such targeted approaches.


   Acknowledgements
 
AMS is supported by the British Heart Foundation.


   Notes
 
1 Tel.: +49 641 99 47 333; fax: +49 641 47 239. Back


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