Publications by authors named "James R Bell"

68 Publications

New Perspectives on Sex Steroid and Mineralocorticoid Receptor Signaling in Cardiac Ischemic Injury.

Front Physiol 2022 29;13:896425. Epub 2022 Jun 29.

Baker Department of Cardiometabolic Health, University of Melbourne VIC, Melbourne, VIC, Australia.

The global burden of ischemic heart disease is burgeoning for both men and women. Although advances have been made, the need for new sex-specific therapies targeting key differences in cardiovascular disease outcomes in men and women remains. Mineralocorticoid receptor directed treatments have been successfully used for blood pressure control and heart failure management and represent a potentially valuable therapeutic option for ischemic cardiac events. Clinical and experimental data indicate that mineralocorticoid excess or inappropriate mineralocorticoid receptor (MR) activation exacerbates ischemic damage, and many of the intracellular response pathways activated in ischemia and subsequent reperfusion are regulated by MR. In experimental contexts, where MR are abrogated genetically or mineralocorticoid signaling is suppressed pharmacologically, ischemic injury is alleviated, and reperfusion recovery is enhanced. In the chronic setting, mineralocorticoid signaling induces fibrosis, oxidative stress, and inflammation, which can predispose to ischemic events and exacerbate post-myocardial infarct pathologies. Whilst a range of cardiac cell types are involved in mineralocorticoid-mediated regulation of cardiac function, cardiomyocyte-specific MR signaling pathways are key. Selective inhibition of cardiomyocyte MR signaling improves electromechanical resilience during ischemia and enhances contractile recovery in reperfusion. Emerging evidence suggests that the MR also contribute to sex-specific aspects of ischemic vulnerability. Indeed, MR interactions with sex steroid receptors may differentially regulate myocardial nitric oxide bioavailability in males and females, potentially determining sex-specific post-ischemic outcomes. There is hence considerable impetus for exploration of MR directed, cell specific therapies for both women and men in order to improve ischemic heart disease outcomes.
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http://dx.doi.org/10.3389/fphys.2022.896425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277457PMC
June 2022

Maternal obesity: influencing the heart right from the start.

J Physiol 2022 07 7;600(13):3007-3008. Epub 2022 Jun 7.

Department of Anatomy & Physiology, The University of Melbourne, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1113/JP283190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327503PMC
July 2022

MEDI: Macronutrient Extraction and Determination from invertebrates, a rapid, cheap and streamlined protocol.

Methods Ecol Evol 2021 Apr 22;12(4):593-601. Epub 2021 Jan 22.

School of Biosciences Cardiff University Cardiff UK.

Macronutrients, comprising carbohydrates, proteins and lipids, underpin many ecological processes, but their quantification in ecological studies is often inaccurate and laborious, requiring large investments of time and bulk samples, which make individual-level studies impossible. This study presents Macronutrient Extraction and Determination from Invertebrates (MEDI), a protocol for the direct, rapid and relatively low-cost determination of macronutrient content from single small macroinvertebrates.Macronutrients were extracted by a sequential process of soaking in 1:12 chloroform:methanol solution to remove lipid and then solubilising tissue in 0.1 M NaOH. Proteins, carbohydrates and lipids were determined by colorimetric assays from the same individual specimens.The limits of detection of MEDI with the equipment and conditions used were 0.067, 0.065 and 0.006 mg/ml for proteins, carbohydrates and lipids respectively. Adjusting the volume of reagents used for extraction and determination can broaden the range of concentrations that can be detected. MEDI successfully identified taxonomic differences in macronutrient content between five insect species.Macronutrient Extraction and Determination from Invertebrates can directly and rapidly determine macronutrient content in tiny (dry mass ~3 mg) and much larger individual invertebrates. Using MEDI, the total macronutrient content of over 50 macroinvertebrates can be determined within around 3 days of collection at a cost of ~$1.35 per sample.
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http://dx.doi.org/10.1111/2041-210X.13551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614113PMC
April 2021

Resolving the identification of weak-flying insects during flight: a coupling between rigorous data processing and biology.

Agric For Entomol 2021 Nov 2;23(4):489-505. Epub 2021 Jun 2.

Rothamsted Insect Survey Rothamsted Research West Common, Harpenden AL5 2JQ U.K.

Bioacoustic methods play an increasingly important role for the detection of insects in a range of surveillance and monitoring programmes.Weak-flying insects evade detection because they do not yield sufficient audio information to capture wingbeat and harmonic frequencies. These inaudible insects often pose a significant threat to food security as pests of key agricultural crops worldwide.Automatic detection of such insects is crucial to the future of crop protection by providing critical information to assess the risk to a crop and the need for preventative measures.We describe an experimental set-up designed to derive audio recordings from a range of weak-flying aphids and beetles using an LED array.A rigorous data processing pipeline was developed to extract meaningful features, linked to morphological characteristics, from the audio and harmonic series for six aphid and two beetle species.An ensemble of over 50 bioacoustic parameters was used to achieve species discrimination with a success rate of 80%. The inclusion of the dominant and fundamental frequencies improved prediction between beetles and aphids because of large differences in wingbeat frequencies.At the species level, error rates were minimized when harmonic features were supplemented by features indicative of differences in species' flight energies.
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http://dx.doi.org/10.1111/afe.12453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596709PMC
November 2021

Author Correction: Moth biomass has fluctuated over 50 years in Britain but lacks a clear trend.

Nat Ecol Evol 2021 Jun;5(6):865-883

Leverhulme Centre for Anthropocene Biodiversity, Department of Biology, University of York, York, UK.

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http://dx.doi.org/10.1038/s41559-021-01449-5DOI Listing
June 2021

Using machine learning to ace cardiovascular risk tests.

Cardiovasc Res 2020 12;116(14):2173-2174

Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia.

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http://dx.doi.org/10.1093/cvr/cvaa305DOI Listing
December 2020

Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality.

J Am Coll Cardiol 2020 09;76(10):1197-1211

Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine and Radiology, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined.

Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF.

Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance.

Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity.

Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.
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http://dx.doi.org/10.1016/j.jacc.2020.07.017DOI Listing
September 2020

Population genetic structure and predominance of cyclical parthenogenesis in the bird cherry-oat aphid in England.

Evol Appl 2020 May 3;13(5):1009-1025. Epub 2020 Feb 3.

Rothamsted Insect Survey, Biointeractions and Crop Protection Department Rothamsted Research Harpenden UK.

Genetic diversity is the determinant for pest species' success and vector competence. Understanding the ecological and evolutionary processes that determine the genetic diversity is fundamental to help identify the spatial scale at which pest populations are best managed. In the present study, we present the first comprehensive analysis of the genetic diversity and evolution of , a major pest of cereals and a main vector of the barley yellow dwarf virus (BYDV), in England. We have used a genotyping-by-sequencing approach to study whether (a) there is any underlying population genetic structure at a national and regional scale in this pest that can disperse long distances; (b) the populations evolve as a response to environmental change and selective pressures; and (c) the populations comprise anholocyclic lineages. Individual were collected using the Rothamsted Insect Survey's suction-trap network at several sites across England between 2004 and 2016 as part of the RIS long-term nationwide surveillance. Results identified two genetic clusters in England that mostly corresponded to a North-South division, although gene flow is ongoing between the two subpopulations. These genetic clusters do not correspond to different life cycle types, and cyclical parthenogenesis is predominant in England. Results also show that there is dispersal with gene flow across England, although there is a reduction between the northern and southern sites with the south-western population being the most genetically differentiated. There is no evidence for isolation by distance and other factors such as primary host distribution, uncommon in the south and absent in the south-west, could influence the dispersal patterns. Finally, results also show no evidence for the evolution of the population, and it is demographically stable despite the ongoing environmental change. These results are discussed in view of their relevance to pest management and the transmission of BYDV.
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http://dx.doi.org/10.1111/eva.12917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232763PMC
May 2020

Are insects declining and at what rate? An analysis of standardised, systematic catches of aphid and moth abundances across Great Britain.

Insect Conserv Divers 2020 Mar 4;13(2):115-126. Epub 2020 Mar 4.

Rothamsted Insect Survey, Rothamsted Research, West Common Harpenden UK.

Although we have known anecdotally that insects have been declining in Great Britain for more than 100 years, insect declines have only been statistically estimated over the last 20 years. Estimation of the rate of those declines is still hotly debated, fuelled by a lack of standardised, systematically collected data.More than 24 million individual moths and aphids collected from 112 light traps and 25 12.2 m suction-traps, respectively, were analysed using mixed models. Our objective was to estimate the long-term trends in both groups based on annual totals recorded every year between 1969 and 2016.The models showed that two paradigms existed: Over 47 years, long-term linear trends showed that moths had declined significantly by -31%, but short-term trends indicated that there were periods of significant decline and recovery in most decades since the 1960s. Conversely, despite aphid annual totals fluctuating widely, this group was in a steady state over the long-term, with a non-significant decline of -7.6%. Sensitivity analysis revealed that moth trends were not driven by a group of abundant species, but the sign of the overall aphid trends may have been driven by three of the most abundant species.The spatial extent of moth trends suggests that they are extremely heterogeneous. Uniquely, moth declines were different among several habitat types, with robust significant declines found in coastal, urban and woodland habitats, but notably not in agricultural, parkland and scrubland habitats. Conversely, aphid trends showed spatial synchrony extending to 338 km, albeit with local variation.
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http://dx.doi.org/10.1111/icad.12412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079554PMC
March 2020

Moth biomass increases and decreases over 50 years in Britain.

Nat Ecol Evol 2019 12 11;3(12):1645-1649. Epub 2019 Nov 11.

Leverhulme Centre for Anthropocene Biodiversity, Department of Biology, University of York, York, UK.

Steep insect biomass declines ('insectageddon') have been widely reported, despite a lack of continuously collected biomass data from replicated long-term monitoring sites. Such severe declines are not supported by the world's longest running insect population database: annual moth biomass estimates from British fixed monitoring sites revealed increasing biomass between 1967 and 1982, followed by gradual decline from 1982 to 2017, with a 2.2-fold net gain in mean biomass between the first (1967-1976) and last decades (2008-2017) of monitoring. High between-year variability and multi-year periodicity in biomass emphasize the need for long-term data to detect trends and identify their causes robustly.
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http://dx.doi.org/10.1038/s41559-019-1028-6DOI Listing
December 2019

Climate-induced phenology shifts linked to range expansions in species with multiple reproductive cycles per year.

Nat Commun 2019 10 24;10(1):4455. Epub 2019 Oct 24.

Department of Biology, University of York, York, YO10 5DD, UK.

Advances in phenology (the annual timing of species' life-cycles) in response to climate change are generally viewed as bioindicators of climate change, but have not been considered as predictors of range expansions. Here, we show that phenology advances combine with the number of reproductive cycles per year (voltinism) to shape abundance and distribution trends in 130 species of British Lepidoptera, in response to ~0.5 °C spring-temperature warming between 1995 and 2014. Early adult emergence in warm years resulted in increased within- and between-year population growth for species with multiple reproductive cycles per year (n = 39 multivoltine species). By contrast, early emergence had neutral or negative consequences for species with a single annual reproductive cycle (n = 91 univoltine species), depending on habitat specialisation. We conclude that phenology advances facilitate polewards range expansions in species exhibiting plasticity for both phenology and voltinism, but may inhibit expansion by less flexible species.
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http://dx.doi.org/10.1038/s41467-019-12479-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813360PMC
October 2019

Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems.

Am J Physiol Cell Physiol 2019 12 2;317(6):C1256-C1267. Epub 2019 Oct 2.

Department of Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.
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http://dx.doi.org/10.1152/ajpcell.00306.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962518PMC
December 2019

Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots.

Compr Physiol 2019 03 14;9(2):457-475. Epub 2019 Mar 14.

The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

As adipose tissue depots are active endocrine organs, they secrete a variety of hormones (including estrogens from white adipose) and inflammatory mediators, which have important implications in numerous obesity-associated diseases. Adipose tissues are broadly characterized as consisting of white, beige, and brown depot types. The endocrine, metabolic, and inflammatory profiles of adipose are depot dependent and influenced by the estrogenic and androgenic status of the adipose tissue. Estrogen receptors mediate both the genomic and nongenomic actions of estrogens and are expressed in the brain, heart, and other peripheral tissues. All three known estrogen receptor α (ERα) and estrogen receptor β (ERβ), and the G-protein coupled estrogen receptor (GPER/GPR30) are expressed in white adipose and can modulate adipose mass. Expression of each receptor is dependent on depot location, adipose cell type, and estrogen levels. Estrogen receptor expression profiles in beige and brown adipocytes are less well established. This review will discuss the effects of estrogens on the differential deposition of the major adipose tissues and the impact of estrogens within white adipose depots. © 2019 American Physiological Society. Compr Physiol 9:457-475, 2019.
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http://dx.doi.org/10.1002/cphy.c180009DOI Listing
March 2019

Spatial and habitat variation in aphid, butterfly, moth and bird phenologies over the last half century.

Glob Chang Biol 2019 06 22;25(6):1982-1994. Epub 2019 Mar 22.

Centre for Ecology & Hydrology, Lancaster Environment Centre, Lancaster, Lancashire, UK.

Global warming has advanced the timing of biological events, potentially leading to disruption across trophic levels. The potential importance of phenological change as a driver of population trends has been suggested. To fully understand the possible impacts, there is a need to quantify the scale of these changes spatially and according to habitat type. We studied the relationship between phenological trends, space and habitat type between 1965 and 2012 using an extensive UK dataset comprising 269 aphid, bird, butterfly and moth species. We modelled phenologies using generalized additive mixed models that included covariates for geographical (latitude, longitude, altitude), temporal (year, season) and habitat terms (woodland, scrub, grassland). Model selection showed that a baseline model with geographical and temporal components explained the variation in phenologies better than either a model in which space and time interacted or a habitat model without spatial terms. This baseline model showed strongly that phenologies shifted progressively earlier over time, that increasing altitude produced later phenologies and that a strong spatial component determined phenological timings, particularly latitude. The seasonal timing of a phenological event, in terms of whether it fell in the first or second half of the year, did not result in substantially different trends for butterflies. For moths, early season phenologies advanced more rapidly than those recorded later. Whilst temporal trends across all habitats resulted in earlier phenologies over time, agricultural habitats produced significantly later phenologies than most other habitats studied, probably because of nonclimatic drivers. A model with a significant habitat-time interaction was the best-fitting model for birds, moths and butterflies, emphasizing that the rates of phenological advance also differ among habitats for these groups. Our results suggest the presence of strong spatial gradients in mean seasonal timing and nonlinear trends towards earlier seasonal timing that varies in form and rate among habitat types.
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http://dx.doi.org/10.1111/gcb.14592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563090PMC
June 2019

Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model.

J Am Heart Assoc 2018 06 1;7(11). Epub 2018 Jun 1.

Department of Physiology, University of Melbourne, Victoria, Australia

Background: Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology.

Methods And Results: The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca operational levels and markedly increased L-type Ca channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed.

Conclusions: Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies.
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http://dx.doi.org/10.1161/JAHA.117.007451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015350PMC
June 2018

The sensitivity of breeding songbirds to changes in seasonal timing is linked to population change but cannot be directly attributed to the effects of trophic asynchrony on productivity.

Glob Chang Biol 2018 03 20;24(3):957-971. Epub 2017 Nov 20.

British Trust for Ornithology, Thetford, UK.

A consequence of climate change has been an advance in the timing of seasonal events. Differences in the rate of advance between trophic levels may result in predators becoming mismatched with prey availability, reducing fitness and potentially driving population declines. Such "trophic asynchrony" is hypothesized to have contributed to recent population declines of long-distance migratory birds in particular. Using spatially extensive survey data from 1983 to 2010 to estimate variation in spring phenology from 280 plant and insect species and the egg-laying phenology of 21 British songbird species, we explored the effects of trophic asynchrony on avian population trends and potential underlying demographic mechanisms. Species which advanced their laying dates least over the last three decades, and were therefore at greatest risk of asynchrony, exhibited the most negative population trends. We expressed asynchrony as the annual variation in bird phenology relative to spring phenology, and related asynchrony to annual avian productivity. In warmer springs, birds were more asynchronous, but productivity was only marginally reduced; long-distance migrants, short-distance migrants and resident bird species all exhibited effects of similar magnitude. Long-term population, but not productivity, declines were greatest among those species whose annual productivity was most greatly reduced by asynchrony. This suggests that population change is not mechanistically driven by the negative effects of asynchrony on productivity. The apparent effects of asynchrony on population trends are therefore either more likely to be strongly expressed via other demographic pathways, or alternatively, are a surrogate for species' sensitivity to other environmental pressures which are the ultimate cause of decline.
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http://dx.doi.org/10.1111/gcb.13960DOI Listing
March 2018

Pericardial adipose and aromatase: A new translational target for aging, obesity and arrhythmogenesis?

J Mol Cell Cardiol 2017 10 16;111:96-101. Epub 2017 Aug 16.

Department of Physiology, School of Biomedical Sciences, University of Melbourne, Australia. Electronic address:

A correlation exists between the extent of pericardial adipose and atrial fibrillation (AF) risk, though the underlying mechanisms remain unclear. Selected adipose depots express high levels of aromatase, capable of converting androgens to estrogens - no studies have investigated aromatase occurrence/expression regulation in pericardial adipose. The Women's Health Initiative reported that estrogen-only therapy in women elevated AF incidence, indicating augmented estrogenic influence may exacerbate cardiac vulnerability. The aim of this study was to identify the occurrence of pericardial adipose aromatase, evaluate the age- and sex-dependency of local cardiac steroid synthesis capacity and seek preliminary experimental evidence of a link between pericardial adipose aromatase capacity and arrhythmogenic vulnerability. Both human atrial appendage and epicardial adipose exhibited immunoblot aromatase expression. In rodents, myocardium and pericardial adipose aromatase expression increased >20-fold relative to young controls. Comparing young, aged and aged-high fat diet animals, a significant positive correlation was determined between the total aromatase content of pericardial adipose and the occurrence/duration of triggered atrial arrhythmias. Incidence and duration of arrhythmias were increased in hearts perfused with 17β-estradiol. This study provides novel report of pericardial adipose aromatase expression. We show that aromatase expression is remarkably upregulated with aging, and aromatase estrogen conversion capacity significantly elevated with obesity-related cardiac adiposity. Our studies suggest an association between adiposity, aromatase estrogenic capacity and atrial arrhythmogenicity - additional investigation is required to establish causality. The potential impact of these findings may be considerable, and suggests that focus on local cardiac steroid conversion (rather than systemic levels) may yield translational outcomes.
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http://dx.doi.org/10.1016/j.yjmcc.2017.08.006DOI Listing
October 2017

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

J Am Heart Assoc 2017 Jun 14;6(6). Epub 2017 Jun 14.

School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.

Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants.

Methods And Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas -knockout mice had smaller hearts. In cultured cardiomyocytes, activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near defined a significant -eQTL for expression.

Conclusions: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1161/JAHA.117.005971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669193PMC
June 2017

Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications.

Pharmacol Res 2017 02 14;116:45-56. Epub 2016 Dec 14.

Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; Department of Pharmacology, University of Melbourne, VIC 3010, Australia; Department of Medicine, Monash University, Clayton 3800, VIC, Australia. Electronic address:

Diabetes mellitus significantly increases the risk of heart failure, independent of coronary artery disease. The mechanisms implicated in the development of diabetic heart disease, commonly termed diabetic cardiomyopathy, are complex, but much of the impact of diabetes on the heart can be attributed to impaired glucose handling. It has been shown that the maladaptive nutrient-sensing hexosamine biosynthesis pathway (HBP) contributes to diabetic complications in many non-cardiac tissues. Glucose metabolism by the HBP leads to enzymatically-regulated, O-linked attachment of a sugar moiety molecule, β-N-acetylglucosamine (O-GlcNAc), to proteins, affecting their biological activity (similar to phosphorylation). In normal physiology, transient activation of HBP/O-GlcNAc mechanisms is an adaptive, protective means to enhance cell survival; interventions that acutely suppress this pathway decrease tolerance to stress. Conversely, chronic dysregulation of HBP/O-GlcNAc mechanisms has been shown to be detrimental in certain pathological settings, including diabetes and cancer. Most of our understanding of the impact of sustained maladaptive HBP and O-GlcNAc protein modifications has been derived from adipose tissue, skeletal muscle and other non-cardiac tissues, as a contributing mechanism to insulin resistance and progression of diabetic complications. However, the long-term consequences of persistent activation of cardiac HBP and O-GlcNAc are not well-understood; therefore, the goal of this timely review is to highlight current understanding of the role of the HBP pathway in development of diabetic cardiomyopathy.
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http://dx.doi.org/10.1016/j.phrs.2016.12.016DOI Listing
February 2017

Dietary omega-6 fatty acid replacement selectively impairs cardiac functional recovery after ischemia in female (but not male) rats.

Am J Physiol Heart Circ Physiol 2016 09 15;311(3):H768-80. Epub 2016 Jul 15.

Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Parkville, Australia;

A definitive understanding of the role of dietary lipids in determining cardioprotection (or cardiodetriment) has been elusive. Randomized trial findings have been variable and sex specificity of dietary interventions has not been determined. In this investigation the sex-selective cardiac functional effects of three diets enriched by omega-3 or omega-6 polyunsaturated fatty acids (PUFA) or enriched to an equivalent extent in saturated fatty acid components were examined in rats after an 8-wk treatment period. In females the myocardial membrane omega-6:omega-3 PUFA ratio was twofold higher than males in the omega-6 diet replacement group. In diets specified to be high in omega-3 PUFA or in saturated fat, this sex difference was not apparent. Isolated cardiomyocyte and heart Langendorff perfusion experiments were performed, and molecular measures of cell viability were assessed. Under basal conditions the contractile performance of omega-6 fed female cardiomyocytes and hearts was reduced compared with males. Omega-6 fed females exhibited impaired systolic resilience after ischemic insult. This response was associated with increased postischemia necrotic cell damage evaluated by coronary lactate dehydrogenase during reperfusion in omega-6 fed females. Cardiac and myocyte functional parameters were not different between omega-3 and saturated fat dietary groups and within these groups there were no discernible sex differences. Our data provide evidence at both the cardiac and cardiomyocyte levels that dietary saturated fatty acid intake replacement with an omega-6 (but not omega-3) enriched diet has selective adverse cardiac effect in females. This finding has potential relevance in relation to women, cardiac risk, and dietary management.
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http://dx.doi.org/10.1152/ajpheart.00690.2015DOI Listing
September 2016

Male and female hypertrophic rat cardiac myocyte functional responses to ischemic stress and β-adrenergic challenge are different.

Biol Sex Differ 2016 7;7:32. Epub 2016 Jul 7.

Department of Physiology, University of Melbourne, Melbourne, Victoria Australia.

Background: Cardiac hypertrophy is the most potent cardiovascular risk factor after age, and relative mortality risk linked with cardiac hypertrophy is greater in women. Ischemic heart disease is the most common form of cardiovascular pathology for both men and women, yet significant differences in incidence and outcomes exist between the sexes. Cardiac hypertrophy and ischemia are frequently occurring dual pathologies. Whether the cellular (cardiomyocyte) mechanisms underlying myocardial damage differ in women and men remains to be determined. In this study, utilizing an in vitro experimental approach, our goal was to examine the proposition that responses of male/female cardiomyocytes to ischemic (and adrenergic) stress may be differentially modulated by the presence of pre-existing cardiac hypertrophy.

Methods: We used a novel normotensive custom-derived hypertrophic heart rat (HHR; vs control strain normal heart rat (NHR)). Cardiomyocyte morphologic and electromechanical functional studies were performed using microfluorimetric techniques involving simulated ischemia/reperfusion protocols.

Results: HHR females exhibited pronounced cardiac/cardiomyocyte enlargement, equivalent to males. Under basal conditions, a lower twitch amplitude in female myocytes was prominent in normal but not in hypertrophic myocytes. The cardiomyocyte Ca(2+) responses to β-adrenergic challenge differed in hypertrophic male and female cardiomyocytes, with the accentuated response in males abrogated in females-even while contractile responses were similar. In simulated ischemia, a marked and selective elevation of end-ischemia Ca(2+) in normal female myocytes was completely suppressed in hypertrophic female myocytes-even though all groups demonstrated similar shifts in myocyte contractile performance. After 30 min of simulated reperfusion, the Ca(2+) desensitization characterizing the male response was distinctively absent in female cardiomyocytes.

Conclusions: Our data demonstrate that cardiac hypertrophy produces dramatically different basal and stress-induced pathophenotypes in female- and male-origin cardiomyocytes. The lower Ca(2+) operational status characteristic of female (vs male) cardiomyocytes comprising normal hearts is not exhibited by myocytes of hypertrophic hearts. After ischemia/reperfusion, availability of activator Ca(2+) is suppressed in female hypertrophic myocytes, whereas sensitivity to Ca(2+) is blunted in male hypertrophic myocytes. These findings demonstrate that selective intervention strategies should be pursued to optimize post-ischemic electromechanical support for male and female hypertrophic hearts.
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http://dx.doi.org/10.1186/s13293-016-0084-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936311PMC
July 2016

Phenological sensitivity to climate across taxa and trophic levels.

Nature 2016 07 29;535(7611):241-5. Epub 2016 Jun 29.

Centre for Ecology &Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster, Lancashire LA1 4AP, UK.

Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5-2.9 days earlier on average), with substantial taxonomic variation (1.1-14.8 days earlier on average).
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http://dx.doi.org/10.1038/nature18608DOI Listing
July 2016

Quantifying interspecific variation in dispersal ability of noctuid moths using an advanced tethered flight technique.

Ecol Evol 2016 01 15;6(1):181-90. Epub 2015 Dec 15.

Department of Agro Ecology Rothamsted Research Harpenden Hertfordshire UK; Environment and Sustainability Institute University of Exeter Penryn Cornwall UK.

Dispersal plays a crucial role in many aspects of species' life histories, yet is often difficult to measure directly. This is particularly true for many insects, especially nocturnal species (e.g. moths) that cannot be easily observed under natural field conditions. Consequently, over the past five decades, laboratory tethered flight techniques have been developed as a means of measuring insect flight duration and speed. However, these previous designs have tended to focus on single species (typically migrant pests), and here we describe an improved apparatus that allows the study of flight ability in a wide range of insect body sizes and types. Obtaining dispersal information from a range of species is crucial for understanding insect population dynamics and range shifts. Our new laboratory tethered flight apparatus automatically records flight duration, speed, and distance of individual insects. The rotational tethered flight mill has very low friction and the arm to which flying insects are attached is extremely lightweight while remaining rigid and strong, permitting both small and large insects to be studied. The apparatus is compact and thus allows many individuals to be studied simultaneously under controlled laboratory conditions. We demonstrate the performance of the apparatus by using the mills to assess the flight capability of 24 species of British noctuid moths, ranging in size from 12-27 mm forewing length (~40-660 mg body mass). We validate the new technique by comparing our tethered flight data with existing information on dispersal ability of noctuids from the published literature and expert opinion. Values for tethered flight variables were in agreement with existing knowledge of dispersal ability in these species, supporting the use of this method to quantify dispersal in insects. Importantly, this new technology opens up the potential to investigate genetic and environmental factors affecting insect dispersal among a wide range of species.
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http://dx.doi.org/10.1002/ece3.1861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716516PMC
January 2016

The Effect of Farmers' Decisions on Pest Control with Bt Crops: A Billion Dollar Game of Strategy.

PLoS Comput Biol 2015 Dec 31;11(12):e1004483. Epub 2015 Dec 31.

Sustainable Soils and Grassland Systems, Rothamsted Research, Harpenden, United Kingdom.

A farmer's decision on whether to control a pest is usually based on the perceived threat of the pest locally and the guidance of commercial advisors. Therefore, farmers in a region are often influenced by similar circumstances, and this can create a coordinated response for pest control that is effective at a landscape scale. This coordinated response is not intentional, but is an emergent property of the system. We propose a framework for understanding the intrinsic feedback mechanisms between the actions of humans and the dynamics of pest populations and demonstrate this framework using the European corn borer, a serious pest in maize crops. We link a model of the European corn borer and a parasite in a landscape with a model that simulates the decisions of individual farmers on what type of maize to grow. Farmers chose whether to grow Bt-maize, which is toxic to the corn borer, or conventional maize for which the seed is cheaper. The problem is akin to the snow-drift problem in game theory; that is to say, if enough farmers choose to grow Bt maize then because the pest is suppressed an individual may benefit from growing conventional maize. We show that the communication network between farmers' and their perceptions of profit and loss affects landscape scale patterns in pest dynamics. We found that although adoption of Bt maize often brings increased financial returns, these rewards oscillate in response to the prevalence of pests.
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http://dx.doi.org/10.1371/journal.pcbi.1004483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705107PMC
December 2015

CaMKIIδ and cardiomyocyte Ca(2+) signalling new perspectives on splice variant targeting.

Clin Exp Pharmacol Physiol 2015 Dec;42(12):1327-32

Department of Physiology, University of Melbourne, Victoria, Australia.

Control of cardiomyocyte cytosolic Ca(2+) levels is crucial in determining inotropic status and ischemia/reperfusion stress response. Responsive to fluctuations in cellular Ca(2+), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase integral to the processes regulating cardiomyocyte Ca(2+) channels/transporters. CaMKII is primarily expressed either in the δB or δC splice variant forms, which may mediate differential influences on cardiomyocyte function and pathological response mechanisms. Increases in myocyte Ca(2+) levels promote the binding of a Ca(2+)/calmodulin complex to CaMKII, to activate the kinase. Activity is also maintained through a series of post-translational modifications within a critical region of the regulatory domain of the protein. Recent data indicate that the post-translational modification status of CaMKIIδB/δC variants may have an important influence on reperfusion outcomes. This study provided the first evidence that the specific type of CaMKII post-translational modification has a role in determining target selectivity of downstream Ca(2+) transporters. The study was also able to demonstrate that the phosphorylated form of CaMKII closely co-localizes with CaMKIIδB in the nuclear/myofilament fraction, contrasting with a co-enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδC . It has also been possible to conclude that a hyper-phosphorylation of CaMKII (Thr287) in reperfused hearts represents a hyper-activation of the CaMKIIδB , which exerts anti-arrhythmic actions through an enhanced capacity to selectively increase sarcoplasmic reticulum Ca(2+) uptake and maintain cytosolic Ca(2+) levels. This suggests that suppression of global CaMKIIδ may not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart.
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http://dx.doi.org/10.1111/1440-1681.12489DOI Listing
December 2015

Cardiomyocyte Mineralocorticoid Receptor Activation Impairs Acute Cardiac Functional Recovery After Ischemic Insult.

Hypertension 2015 Nov 8;66(5):970-7. Epub 2015 Sep 8.

From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).

Loss of mineralocorticoid receptor signaling selectively in cardiomyocytes can ameliorate cardiac fibrotic and inflammatory responses caused by excess mineralocorticoids. The aim of this study was to characterize the role of cardiomyocyte mineralocorticoid receptor signaling in ischemia-reperfusion injury and recovery and to identify a role of mineralocorticoid receptor modulation of cardiac function. Wild-type and cardiomyocyte mineralocorticoid receptor knockout mice (8 weeks) were uninephrectomized and maintained on (1) high salt (0.9% NaCl, 0.4% KCl) or (2) high salt plus deoxycorticosterone pellet (0.3 mg/d, 0.9% NaCl, 0.4% KCl). After 8 weeks of treatment, hearts were isolated and subjected to 20 minutes of global ischemia plus 45 minutes of reperfusion. Mineralocorticoid excess increased peak contracture during ischemia regardless of genotype. Recovery of left ventricular developed pressure and rates of contraction and relaxation post ischemia-reperfusion were greater in knockout versus wild-type hearts. The incidence of arrhythmic activity during early reperfusion was significantly higher in wild-type than in knockout hearts. Levels of autophosphorylated Ca(2+)/calmodulin protein kinase II (Thr287) were elevated in hearts from wild-type versus knockout mice and associated with increased sodium hydrogen exchanger-1 expression. These findings demonstrate that cardiomyocyte-specific mineralocorticoid receptor-dependent signaling contributes to electromechanical vulnerability in acute ischemia-reperfusion via a mechanism involving Ca(2+)/calmodulin protein kinase II activation in association with upstream alteration in expression regulation of the sodium hydrogen exchanger-1.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05981DOI Listing
November 2015

Organic Farming: Biodiversity Impacts Can Depend on Dispersal Characteristics and Landscape Context.

PLoS One 2015 26;10(8):e0135921. Epub 2015 Aug 26.

Wildlife Conservation Research Unit, The Recanati-Kaplan Centre, Department of Zoology, University of Oxford, Tubney, United Kingdom.

Organic farming, a low intensity system, may offer benefits for a range of taxa, but what affects the extent of those benefits is imperfectly understood. We explored the effects of organic farming and landscape on the activity density and species density of spiders and carabid beetles, using a large sample of paired organic and conventional farms in the UK. Spider activity density and species density were influenced by both farming system and surrounding landscape. Hunting spiders, which tend to have lower dispersal capabilities, had higher activity density, and more species were captured, on organic compared to conventional farms. There was also evidence for an interaction, as the farming system effect was particularly marked in the cropped area before harvest and was more pronounced in complex landscapes (those with little arable land). There was no evidence for any effect of farming system or landscape on web-building spiders (which include the linyphiids, many of which have high dispersal capabilities). For carabid beetles, the farming system effects were inconsistent. Before harvest, higher activity densities were observed in the crops on organic farms compared with conventional farms. After harvest, no difference was detected in the cropped area, but more carabids were captured on conventional compared to organic boundaries. Carabids were more species-dense in complex landscapes, and farming system did not affect this. There was little evidence that non-cropped habitat differences explained the farming system effects for either spiders or carabid beetles. For spiders, the farming system effects in the cropped area were probably largely attributable to differences in crop management; reduced inputs of pesticides (herbicides and insecticides) and fertilisers are possible influences, and there was some evidence for an effect of non-crop plant species richness on hunting spider activity density. The benefits of organic farming may be greatest for taxa with lower dispersal abilities generally. The evidence for interactions among landscape and farming system in their effects on spiders highlights the importance of developing strategies for managing farmland at the landscape-scale for most effective conservation of biodiversity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135921PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550245PMC
June 2016

The role of CaMKII in diabetic heart dysfunction.

Heart Fail Rev 2015 Sep;20(5):589-600

Department of Physiology, University of Otago, PO Box 56, Dunedin, New Zealand.

Diabetes mellitus (DM) is an increasing epidemic that places a significant burden on health services worldwide. The incidence of heart failure (HF) is significantly higher in diabetic patients compared to non-diabetic patients. One underlying mechanism proposed for the link between DM and HF is activation of calmodulin-dependent protein kinase (CaMKIIδ). CaMKIIδ mediates ion channel function and Ca(2+) handling during excitation-contraction and excitation-transcription coupling in the myocardium. CaMKIIδ activity is up-regulated in the myocardium of diabetic patients and mouse models of diabetes, where it promotes pathological signaling that includes hypertrophy, fibrosis and apoptosis. Pharmacological inhibition and knockout models of CaMKIIδ have shown some promise of a potential therapeutic benefit of CaMKIIδ inhibition, with protection against cardiac hypertrophy and apoptosis reported. This review will highlight the pathological role of CaMKIIδ in diabetes and discuss CaMKIIδ as a therapeutic target in DM, and also the effects of exercise on CaMKIIδ.
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http://dx.doi.org/10.1007/s10741-015-9498-3DOI Listing
September 2015

Myocardial and cardiomyocyte stress resilience is enhanced in aromatase-deficient female mouse hearts through CaMKIIδ activation.

Endocrinology 2015 Apr 27;156(4):1429-40. Epub 2015 Jan 27.

Cardiac Phenomics Laboratory (J.R.B., G.B.B., A.C.W., A.J.A.R., C.L.C., K.M.M., L.M.D.D.), Department of Physiology, and The Florey Institute of Neuroscience and Mental Health (W.C.B.), University of Melbourne, Victoria 3010, Australia; Monash Institute of Medical Research-Prince Henry's Institute of Medical Research (E.R.S.), Clayton 3168, Victoria, Australia; and Department of Physiology (K.M.M.), University of Auckland, 1142 Auckland, New Zealand.

The role of sex steroids in cardioprotection is contentious, with large clinical trials investigating hormone supplementation failing to deliver outcomes expected from observational studies. Mechanistic understanding of androgen/estrogen myocardial actions is lacking. Using a genetic model of aromatase tissue deficiency (ArKO) in female mice, the goal of this investigation was to evaluate the capacity of a shift in cardiac endogenous steroid conversion to influence ischemia-reperfusion resilience by optimizing cardiomyocyte Ca2+ handling responses. In isolated normoxic cardiomyocytes, basal Ca2+ transient amplitude and extent of shortening were greater in ArKO myocytes, with preservation of diastolic Ca2+ levels. Isolated ArKO cardiomyocytes exposed to a high Ca2+ load exhibited greater Ca2+ transient and contractile amplitudes, associated with a greater postrest spontaneous sarcoplasmic reticulum Ca2+ load-release. Microarray differential gene expression analysis of normoxic ventricular tissues from ArKO vs wild-type identified a significant influence of aromatase on genes involved in cardiac Ca2+ handling and signaling [including calmodulin dependent kinase II (CaMKII)-δ], myofilament structure and function, glucose uptake and signaling, and enzymes controlling phosphorylation-specific posttranslational modification status. CaMKII expression was not changed in ventricular tissues, although CaMKIIδ activation and phosphorylation of downstream targets was enhanced in ArKO hearts subjected to ischemia-reperfusion. Overall, this investigation shows that relative withdrawal of estrogen in favor of testosterone through genetically induced tissue aromatase deficiency in females modifies the gene expression profile to effect inotropic support via optimized Ca2+ handling in response to stress, with a modest impact on basal function. Consideration of aromatase inhibition, acutely or chronically, may have a role in cardioprotection, of particular relevance to women.
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http://dx.doi.org/10.1210/en.2014-1700DOI Listing
April 2015

Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart.

Int J Cardiol 2015 Feb 26;181:288-96. Epub 2014 Nov 26.

Department of Physiology, University of Melbourne, Victoria, Australia. Electronic address:

Background: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts.

Methods And Results: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p<0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively.

Conclusions: This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.
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http://dx.doi.org/10.1016/j.ijcard.2014.11.159DOI Listing
February 2015
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