Redox Signaling in Cardiac Physiology and Pathology

Abstract

T he concept that oxidative stress-a pathologically high level of oxidant species in cells-may drive cardiovascular disease progression has led to many clinical trials of interventions, such as antioxidant vitamins. These, however, failed to show efficacy in reducing disease risk and progression. Part of the reason may be the focus on oxidative stress as detrimental neglected the wider role of redox balance and reactive oxygen species (ROS) and reactive nitrogen species in cellular (patho)physiology. Redox signaling-defined as the specific, usually reversible, oxidation/reduction modification of cellular signaling pathway components by a reactive species 1 -is increasingly appreciated as centrally important in many physiological and pathological processes. The main ROS involved in redox signaling are the superoxide anion (O 2 − ) and the more stable nonradical hydrogen peroxide (H 2 O 2 ) to which it dismutates, whereas more powerful oxidants such as hydroxyl are so reactive they are unlikely to be specific or reversible. Redox signaling also involves reactive nitrogen species such as NO and peroxynitrite, the latter being formed from the reaction of O 2 − with NO. 2In the heart, redox signaling is involved in physiological processes (eg, excitation-contraction coupling [ECC], cell differentiation), homoeostatic and stress response pathways (eg, adaptation to hypoxia/ischemia), and pathology (eg, adverse cardiac remodeling, fibrosis). This review covers recent advances in understanding the regulation of production of signaling ROS, their mechanisms of action and molecular targets in cardiac cells, and their involvement in cardiac physiopathology. We focus mainly on cardiomyocytes but redox signaling in other cells (eg, fibroblasts, endothelial cells), and functional cross talks among these are also important. Reactive nitrogen species-dependent regulation has been reviewed elsewhere. 2 ROS SourcesROS are generated as a by-product of cellular respiration and metabolism or by specialized enzymes that seem to be centrally involved in redox signaling. The signaling effects of ROS are influenced by their site of production, precise species, local concentration, and cell compartment-specific antioxidant pools. Major ROS sources in the heart and other tissues include the mitochondrial electron transport chain (ETC), other mitochondrial and metabolic enzymes, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs), and uncoupled NO synthases (NOS). Mitochondrial ETCElectron leakage from the ETC causes 1-electron reduction of O 2 to O 2 − (instead of reduction to H 2 O). Although considered to be because of an electron leak, such ROS may nevertheless contribute to homeostatic redox signals. ROS levels increase significantly during mitochondrial dysfunction. They can trigger the mitochondrial permeability transition (MPT) and lead to further ROS release-termed ROS-induced ROS release 3 -which propagates and amplifies ROS production and effects. ROS from non-ETC sources (eg, Noxs) may also stimulate ETC-depende...

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

“…405/488-nm excitation ratio images were created and analyzed using ImageJ software (National Institutes of Health, Bethesda, MD) as 16-bit TIFF files. After normalization of the ratiometric signals to R max (1) and R min (0) to obtain the fractional oxidation, F ox , of the sensor, the change in GRX1-roGFP or roGFP-ORP1 signal from baseline (⌬F ox ) was determined during exposure to H 2 O 2 for statistical analysis unless otherwise indicated. 50% duration of recovery of the GSH pool was determined as the time from the peak GRX1-roGFP oxidation to half recovery to the baseline ratio.…”

“…superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1)(2)(3)(4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.…”

Serum free thiols in chronic heart failure

“…(6,7) These processes are accompanied by perturbations of cardiac physiology due to progressive changes in redox signalling at multiple levels. (8) Systemic oxidative stress can be measured as the depletion of the free thiol pool in serum. (9) In contrast to the intracellular pool, which mainly consists of low molecular weight (LMW) thiols, in serum LMW thiols have a small share and protein thiols predominate.…”

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

“…The hexosamine biosynthesis pathway, a growth and protein synthesis pathway, is increased in HF and contributes to cardiac hypertrophy and remodelling. The PPP is also up‐regulated to produce increased levels of NADPH, which are required for anti‐oxidative defence at low levels of ROS (Burgoyne et al ., 2012), but may contribute to oxidative stress when ROS levels are high. G6P will also enter the glycolytic pathway to produce pyruvate.…”