ORCID Profile
0000-0001-8788-3683
Current Organisations
King's College London
,
University of New South Wales
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Publisher: Frontiers Media SA
Date: 21-04-2023
DOI: 10.3389/FCVM.2023.1072042
Abstract: Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome—a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
Publisher: American Physiological Society
Date: 09-2020
DOI: 10.1152/AJPREGU.00322.2019
Abstract: How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates rotein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac “death proteins” were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (−20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), P 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60–90% above control) in WD mice ( P 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippoc al TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically “benign” stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).
Publisher: Springer International Publishing
Date: 2023
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.LFS.2022.121137
Abstract: Evolving type 2 diabetes (T2D) may influence locomotion and affective state, promoting metabolic dysfunction. We examined behaviour and neurobiology in a model of T2D, testing for benefits with dietary n-3 polyunsaturated fatty acid (PUFA). Male C57Bl/6 mice received vehicle or 75 mg/kg streptozotocin (STZ) and 21 wks of control or Western diets (43 % fat, 40 % carbohydrate, 17 % protein). Sub-sets received dietary α-linolenic acid (ALA 10 % of fat intake) for 6 wks. Behaviour was examined via open field and sucrose preference tests, and hippoc al and frontal cortex (FC) leptin and dopamine levels and inflammatory signalling assessed. T2D mice exhibited weight gain (+15 %), hyperglycemia (+35 %), hyperinsulinemia (+60 %) and insulin-resistance (+80 % higher HOMA-IR), together with anxiety-like behaviour (without anhedonia) that appeared independent of body weight and glycemic status. Cortical leptin declined whereas receptor mRNA increased. Supplementation with ALA did not influence metabolic state, while enhancing locomotion and reducing anxiety-like behaviours in healthy but not T2D mice. Hippoc al dopamine was selectively increased by ALA in T2D mice, with a trend to reduced circulating leptin in both groups. Across all groups, anxiety-like behaviour was associated with declining cortical and hippoc al leptin levels and increasing receptor mRNA, while declining dopamine levels were accompanied by decreased dopamine/serotonin receptor transcripts. Chronic T2D induced anxiogenesis in mice appears to be independent of metabolic homeostasis but linked to central leptin-resistance, together with disturbed dopamine and serotonin signalling. Despite anxiolytic effects of ALA in healthy mice, no metabolic or behavioural benefits were evident in T2D.
Publisher: Elsevier BV
Date: 06-0006
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: Wiley
Date: 04-09-2022
DOI: 10.1002/JNR.25115
Abstract: Psychosocial stress promotes and links mood and cardiovascular disorders in a sex‐specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippoc al monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippoc al Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females and repression of hippoc al Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti‐inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress‐related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex‐specific mechanisms and potential approaches to stress‐dependent disease.
Publisher: Cambridge University Press (CUP)
Date: 16-04-2022
DOI: 10.1017/S0007114521001276
Abstract: Linoleic acid (LA), an essential n -6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA 1·44 % energy from LA) or high LA (HLA 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 ( n 6–8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n -3 FA in males, while maternal and postnatal HLA diets decreased total plasma n -3 FA in females. α -Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n -6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure–volume relationship (PVR), and increased cardiac Col1a1 , Col3a1 , Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
Publisher: IEEE
Date: 06-2016
DOI: 10.1109/MDM.2016.40
Publisher: MDPI AG
Date: 15-08-2017
DOI: 10.3390/JSAN6030017
Publisher: Wiley
Date: 22-10-2019
DOI: 10.1113/EP088024
Publisher: Wiley
Date: 20-07-2022
DOI: 10.1111/EJN.15747
Abstract: Stress resilience, and behavioural and cardiovascular impacts of chronic stress, are theorised to involve integrated neuro‐endocrine/inflammatory/transmitter/trophin signalling. We tested for this integration, and whether behaviour/emotionality, together with myocardial ischaemic tolerance, are consistently linked to these pathways across erse conditions in male C57Bl/6 mice. This included Restraint Stress (RS), 1 h restraint/day for 14 days Chronic Unpredictable Mild Stress (CUMS), seven stressors randomised over 21 days Social Stress (SS), 35 days social isolation with brief social encounters in final 13 days and Control conditions (CTRL un‐stressed mice). Behaviour was assessed via open field (OFT) and sucrose preference (SPT) tests, and neurobiology from frontal cortex (FC) and hippoc al transcripts. Endocrine factors, and function and ischaemic tolerance in isolated hearts, were also measured. Model characteristics ranged from no behavioural or myocardial changes with homotypic RS, to increased emotionality and cardiac ischaemic injury (with apparently distinct endocrine/neurobiological profiles) in CUMS and SS models. Highly integrated expression of HPA axis, neuro‐inflammatory, BDNF, monoamine, GABA, cannabinoid and opioid signalling genes was confirmed across conditions, and consistent otentially causal correlations identified for (i) locomotor activity (noradrenaline, ghrelin FC Crhr1 , Tnfrsf1b , Il33 , Nfkb1 , Maoa , Gabra1 hippoc al Il33 ) (ii) thigmotaxis (adrenaline, leptin) (iii) anxiety‐like behaviour (adrenaline, leptin FC Tnfrsf1a hippoc al Il33 ) (iv) depressive‐like behaviour (ghrelin FC/hippoc al s100a8 ) and (v) cardiac stress‐resistance (noradrenaline, leptin FC Il33 , Tnfrsf1b , Htr1a , Gabra1 , Gabrg2 hippoc al Il33 , Tnfrsf1a , Maoa , Drd2 ). Data support highly integrated pathway responses to stress, and consistent adipokine, sympatho‐adrenergic, inflammatory and monoamine involvement in mood and myocardial disturbances across erse conditions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tessa Helman.