Anita Ayer | University of South Wales (original) (raw)

Papers by Anita Ayer

Physiological reviews, Oct 1, 2016

Heme oxygenases are composed of two isozymes, Hmox1 and Hmox2, that catalyze the degradation of h... more Heme oxygenases are composed of two isozymes, Hmox1 and Hmox2, that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, the latter of which is subsequently converted to bilirubin. While initially considered to be waste products, CO and biliverdin/bilirubin have been shown over the last 20 years to modulate key cellular processes, such as inflammation, cell proliferation, and apoptosis, as well as antioxidant defense. This shift in paradigm has led to the importance of heme oxygenases and their products in cell physiology now being well accepted. The identification of the two human cases thus far of heme oxygenase deficiency and the generation of mice deficient in Hmox1 or Hmox2 have reiterated a role for these enzymes in both normal cell function and disease pathogenesis, especially in the context of cardiovascular disease. This review covers the current knowledge on the function of both Hmox1 and Hmox2 at both a cellular and tissue level in the c...

Annual Review of Nutrition, 2015

Coenzyme Q (CoQ) is an essential lipid of cells present in all cellular compartments. The functio... more Coenzyme Q (CoQ) is an essential lipid of cells present in all cellular compartments. The functions of CoQ in mitochondrial respiration and as an antioxidant are established, although the lipid likely has additional, presently unknown, roles. While the therapeutic utility of CoQ10 supplements is recognized in the rare cases of primary CoQ10 deficiencies, a potential role for CoQ10 supplements in cardiovascular disease, particularly heart failure, has also been studied for over 40 years. This review summarizes our current knowledge in these areas derived from animal studies and human trials. Current evidence for a benefit of CoQ10 supplements in diseases other than primary CoQ10 deficiencies is insufficient.

Free Radical Biology and Medicine, 2015

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failur... more Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signalling exaggerated diabetes-induced cardiomyopathy; associated with upregulated NADPH oxidase. To examine whether chronic supplementation with the antioxidant coenzyme Q10 (CoQ10) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signalling. Diabetes was induced in 6-week-old non-transgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ10 supplementation commenced (10mg/kg i.p., 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine) and concentrations of CoQ9 and CoQ10 were determined. LV NADPH oxidase (Nox2 gene expression and activity, on lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ10. Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor and β-myosin heavy chain, were all attenuated by CoQ10. Chronic CoQ10 supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signalling. Given CoQ10 supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ10 supplementation may be an attractive adjunct therapy for diabetic heart failure.

G3 (Bethesda, Md.), Jan 9, 2013

The heat-shock response in cells, involving increased transcription of a specific set of genes in... more The heat-shock response in cells, involving increased transcription of a specific set of genes in response to a sudden increase in temperature, is a highly conserved biological response occurring in all organisms. Despite considerable attention to the processes activated during heat shock, less is known about the role of genes in survival of a sudden temperature increase. Saccharomyces cerevisiae genes involved in the maintenance of heat-shock resistance in exponential and stationary phase were identified by screening the homozygous diploid deletants in nonessential genes and the heterozygous diploid mutants in essential genes for survival after a sudden shift in temperature from 30 to 50°. More than a thousand genes were identified that led to altered sensitivity to heat shock, with little overlap between them and those previously identified to affect thermotolerance. There was also little overlap with genes that are activated or repressed during heat-shock, with only 5% of them re...

PLoS ONE, 2013

Responses to many growth and stress conditions are assumed to act via changes to the cellular red... more Responses to many growth and stress conditions are assumed to act via changes to the cellular redox status. However, direct measurement of pH-adjusted redox state during growth and stress has never been carried out. Organellar redox state (E GSH ) was measured using the fluorescent probes roGFP2 and pHluorin in Saccharomyces cerevisiae. In particular, we investigated changes in organellar redox state in response to various growth and stress conditions to better understand the relationship between redox-, oxidative-and environmental stress response systems. E GSH values of the cytosol, mitochondrial matrix and peroxisome were determined in exponential and stationary phase in various media. These values (2340 to 2350 mV) were more reducing than previously reported. Interestingly, sub-cellular redox state remained unchanged when cells were challenged with stresses previously reported to affect redox homeostasis. Only hydrogen peroxide and heat stress significantly altered organellar redox state. Hydrogen peroxide stress altered the redox state of the glutathione disulfide/glutathione couple (GSSG, 2H + /2GSH) and pH. Recovery from moderate hydrogen peroxide stress was most rapid in the cytosol, followed by the mitochondrial matrix, with the peroxisome the least able to recover. Conversely, the bulk of the redox shift observed during heat stress resulted from alterations in pH and not the GSSG, 2H + /2GSH couple. This study presents the first direct measurement of pH-adjusted redox state in sub-cellular compartments during growth and stress conditions. Redox state is distinctly regulated in organelles and data presented challenge the notion that perturbation of redox state is central in the response to many stress conditions.

PLoS ONE, 2012

Maintenance of an optimal redox environment is critical for appropriate functioning of cellular p... more Maintenance of an optimal redox environment is critical for appropriate functioning of cellular processes and cell survival. Despite the importance of maintaining redox homeostasis, it is not clear how the optimal redox potential is sensed and set, and the processes that impact redox on a cellular/organellar level are poorly understood. The genetic bases of cellular redox homeostasis were investigated using a green fluorescent protein (GFP) based redox probe, roGFP2 and a pH sensitive GFPbased probe, pHluorin. The use of roGFP2, in conjunction with pHluorin, enabled determination of pH-adjusted sub-cellular redox potential in a non-invasive and real-time manner. A genome-wide screen using both the non-essential and essential gene collections was carried out in Saccharomyces cerevisiae using cytosolic-roGFP2 to identify factors essential for maintenance of cytosolic redox state under steady-state conditions. 102 genes of diverse function were identified that are required for maintenance of cytosolic redox state. Mutations in these genes led to shifts in the half-cell glutathione redox potential by 75-10 mV. Interestingly, some specific oxidative stress-response processes were identified as over-represented in the data set. Further investigation of the role of oxidative stress-responsive systems in sub-cellular redox homeostasis was conducted using roGFP2 constructs targeted to the mitochondrial matrix and peroxisome and E GSH was measured in cells in exponential and stationary phase. Analyses allowed for the identification of key redox systems on a sub-cellular level and the identification of novel genes involved in the regulation of cellular redox homeostasis.

FEMS Yeast Research, 2014

Ageing cells undergo changes in redox homeostasis and acquire high levels of reactive oxygen spec... more Ageing cells undergo changes in redox homeostasis and acquire high levels of reactive oxygen species (ROS). Because accumulation of ROS involves a change in redox state of cells, functions that are involved in setting redox and maintaining redox homeostasis are very relevant to an understanding of the possible roles of redox homeostasis and ROS in ageing. This review discusses these aspects of ROS in relation to replicative ageing in the model organism Saccharomyces cerevisiae, with reference to ROS generated in cells; cellular responses to oxidative stress; and how cells maintain redox homeostasis in different cellular compartments. It also considers when ROS generation begins as cells age, which ROS species are relevant to ageing and which cellular compartments and processes may contribute ROS to the ageing process. The discussion also covers the heterogeneity of cells with respect to ROS accumulation at particular cell ages, and the possibility of testing the oxidative theory of ageing in yeast cells.

…, Jan 1, 2011

There are almost as many definitions of systems biology as there are workers in the field and we ... more There are almost as many definitions of systems biology as there are workers in the field and we won't attempt to add any further definition. In order to obtain an holistic view to the functioning of all of the processes in a cell, it is important to obtain sufficient data to understand the relationships between the many components that make up the cell.

Aging Research in Yeast, Jan 1, 2012

Oxidative damage to cellular constituents has frequently been associated with aging in a wide ran... more Oxidative damage to cellular constituents has frequently been associated with aging in a wide range of organisms. The power of yeast genetics and biochemistry has provided the opportunity to analyse in some detail how reactive oxygen and nitrogen species arise in cells, how cells respond to the damage that these reactive species cause, and to begin to dissect how these species may be involved in the ageing process. This chapter reviews the major sources of reactive oxygen species that occur in yeast cells, the damage they cause and how cells sense and respond to this damage.

Biodiscovery and industrial …, Jan 1, 2010

Free Radical Biology …, Jan 1, 2010

Glutathione (GSH) is a key redox buffer and protectant. Growth (approx. one or two divisions) of ... more Glutathione (GSH) is a key redox buffer and protectant. Growth (approx. one or two divisions) of cells lacking γ-glutamylcysteine synthetase (gsh1) in the absence of GSH led to irreversible respiratory incompetency in all cells, and after five divisions 75% of cells completely lacked mitochondrial DNA (mtDNA). The level of GSH required to allow continuous growth was distinct from that required to prevent loss of mtDNA. GSH limitation led to a change in the transcript levels of 190 genes, including 30 genes regulated by the Aft1p and/or Aft2p transcription factors, which regulate the cellular response to changes in iron availability. Disruption of AFT1 but not AFT2 in gsh1 cells afforded a protective effect on maintenance of respiratory competency, as did overexpression of GRX3 or GRX4 (encoding monothiol glutaredoxins that act as negative regulators of Aft1p). Importantly, an iron-independent mechanism (~30%) was also observed to mediate GSH-dependent mtDNA loss. Analysis of the redox environment in the cytosol, mitochondrial matrix, and intermembrane space (IMS) found that the cytosol was most severely and rapidly affected by GSH depletion. GSH may also modulate the redox environment of the IMS. The implications of altered GSH homeostasis for maintenance of mtDNA, compartmental redox, and the pathophysiology of certain diseases are discussed.