Free radicals and redox signalling in cardiovascular disease

The generation of reactive oxygen species (ROS) is an inevitable consequence of life in an aerobic environment. ROS are characterised by their high chemical reactivity and include both free radicals (that is, species with one or more unpaired electrons, such as superoxide (O2 . −) and hydroxyl radicals (OH . )), and non-radical species such as hydrogen peroxide (H2O2). In health, there is a balance between ROS generation and the activity of enzymatic and non-enzymatic antioxidant systems that scavenge or reduce ROS concentrations.1 Redox imbalance caused by increased ROS production and/or reduced antioxidant reserve causes oxidative stress—that is, an enhanced susceptibility of biological molecules and membranes to reaction with ROS. Traditionally, oxidative stress has been considered deleterious due to free radical induced oxidation and damage of macromolecules, membranes and DNA. ROS generation by phagocytic cells such as neutrophils is a pivotal component of their antimicrobial actions and as such deleterious for ingested organisms, but is, however, clearly beneficial for the host. On the other hand, the restoration of oxygen supply during myocardial reperfusion after prolonged ischaemia is accompanied by a burst of free radical production that is damaging for the heart.2 Oxidative stress induced damage includes acceleration of cell death through apoptosis and necrosis, mechanisms that may also be of relevance in advanced heart failure. Recently, however, it has been recognised that oxidative stress may exert more subtle modulatory effects. Firstly, the tightly regulated production of ROS can modulate the activity of diverse intracellular molecules and signalling pathways (a mechanism commonly termed “redox signalling”), with the potential to induce highly specific acute and chronic changes in cell phenotype.3 This use of oxygen species to transmit biological information provides at least a teleological explanation for the widespread occurrence of ROS even in health. Secondly, inactivation …

[1]  A. Shah,et al.  Contrasting Roles of NADPH Oxidase Isoforms in Pressure-Overload Versus Angiotensin II–Induced Cardiac Hypertrophy , 2003, Circulation research.

[2]  K. Rockett,et al.  Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. , 2003, The Journal of clinical investigation.

[3]  A. Shah,et al.  Increased myocardial NADPH oxidase activity in human heart failure. , 2003, Journal of the American College of Cardiology.

[4]  Steven M Holland,et al.  Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. , 2003, The Journal of clinical investigation.

[5]  D. Harrison,et al.  Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease: Relation to Endothelium-Dependent Vasodilation , 2003, Circulation.

[6]  S. Devaraj,et al.  Antioxidants and atherosclerosis: don't throw out the baby with the bath water. , 2003, Circulation.

[7]  K. Channon,et al.  Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus: Role of NAD(P)H Oxidase and Endothelial Nitric Oxide Synthase , 2002, Circulation.

[8]  H. Tsutsui,et al.  Oxidative stress in heart failure: the role of mitochondria. , 2001, Internal medicine.

[9]  P. Klatt,et al.  Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. , 2000, European journal of biochemistry.

[10]  K. Channon,et al.  Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. , 2000, Circulation research.

[11]  B. Halliwell,et al.  Free Radicals and Antioxidants in the Year 2000: A Historical Look to the Future , 2000, Annals of the New York Academy of Sciences.

[12]  G. Ambrosio,et al.  Reperfusion injury: experimental evidence and clinical implications. , 1999, American heart journal.

[13]  T. Finkel.  Signal transduction by reactive oxygen species in non‐phagocytic cells , 1999, Journal of leukocyte biology.

[14]  P. Kaminski,et al.  Inhibition of rat cardiac muscle contraction and mitochondrial respiration by endogenous peroxynitrite formation during posthypoxic reoxygenation. , 1998, Circulation research.

[15]  D. Harrison,et al.  Cellular and molecular mechanisms of endothelial cell dysfunction. , 1997, The Journal of clinical investigation.

[16]  E. Marbán,et al.  Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. , 1996, Circulation.

[17]  J E Thompson,et al.  Don't throw out the baby with the bath water: A perspective on carotid endarterectomy , 1986 .