Kristine is a lecturer within the University of Technology Sydney, Faculty of Science. She is currently coordinating the first year core Science Subject – Cell Biology and Genetics.
Kristine has completed a Bachelor of Science (Hons) majoring in Biochemistry at the University of Western Australia. She then moved to Sydney and completed a PhD study (“Molecular pathways of androgen action in the male cardiovascular system) under the supervision of Prof Alison Heather, Prof David Celermajer and Prof David Handelsman, at the University of Sydney. Kristine presented her PhD results at the Cardiac Society of Australia and New Zealand (CSANZ) and was awarded the prestigious CSANZ Ralph Reader Prize.
Her early postdoctoral work in Prof Kerry-Anne Rye research laboratory at the Heart Research Institute (Sydney) focused on characterizing the anti-inflammatory properties of high density lipoprotein (HDL). In 2011, she received a UTS Chancellor’s Postdoctoral Research Fellowship where she evaluated the anti-inflammatory effects of HDL in suppressing inflammation that underlies diet-induced insulin resistance.
Kristine current interest is to find targets/compounds to treat and/or reduce chronic inflammation that underlies insulin resistance, type 2 diabetes and atherosclerosis. Experimental approaches are based on molecular, cellular and animal models.
Member of Australian Diabetes Society
Committee member of the New Horizons
Can supervise: YES
- Therapeutic potential of anti-inflammatory and/or antioxidant compounds in NAFLD, type 2 diabetes and atherosclerosis
- Therapeutic potential of complementary and alternative medicines in NAFLD, type 2 diabetes and atherosclerosis
Cell Biology and Genetics - Subject Coordinator
Histology - Lecturer
Anatomical Pathology - Lecturer
Human Pathophysiologies - Lecturer
McGrath, KC, Li, X, Twigg, SM & Heather, AK 2020, 'Apolipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice', PLOS ONE, vol. 15, no. 1.View/Download from: Publisher's site
Nguyen, T, Li, GE, Chen, H, Cranfield, CG, McGrath, KC & Gorrie, CA 2019, 'Neurological effects in the offspring after switching from tobacco cigarettes to e-cigarettes during pregnancy in a mouse model.', Toxicological Sciences, vol. 172, no. 1, pp. 191-200.View/Download from: Publisher's site
BACKGROUND:Maternal smoking is currently a public health concern and has been associated with a number of complications in the offspring. E-cigarettes are gaining popularity as a 'safer' alternative to tobacco cigarettes during pregnancy, however, there are a limited number of studies to suggest that it is actually 'safe'. STUDY DESIGN:Balb/C female mice were exposed to ambient air (n = 8; Sham), or tobacco cigarette smoke (n = 8; SE) before gestation, during gestation and lactation. A third group was exposed to cigarette smoke before gestation followed by e-cigarette aerosols during gestation and lactation (n = 8; Switch). Male offspring (12-week old, n = 10-14/group) underwent behavioural assessments to investigate short-term memory, anxiety and activity using the novel object recognition (NOR) and elevated plus maze (EPM) tests. Brains were collected at postnatal day (P)1, P20 and Week13 for global DNA methylation, epigenetic gene expression, and neuronal cell counts. RESULTS:The offspring from mothers switching to e-cigarettes exhibited no change in exploration/activity, but showed a decrease in global DNA methylation, Aurora Kinase (Aurk) A and AurkB gene expression and a reduction in neuronal cell numbers in the cornu ammonis 1 region of the dorsal hippocampus compared to the SE group. CONCLUSIONS:Continuous tobacco cigarette smoke exposure during pregnancy resulted in marked neurological deficits in the offspring. Switching to e-cigarettes during pregnancy reduced these neurological deficits compared to cigarette smoke exposure. However, neurological changes were still observed, so we therefore conclude that e-cigarette use during pregnancy is not advised.
Cooper, ER, McGrath, KCY, Li, X & Heather, AK 2018, 'Androgen Bioassay for the Detection of Nonlabeled Androgenic Compounds in Nutritional Supplements.', International journal of sport nutrition and exercise metabolism, vol. 28, no. 1, pp. 10-18.View/Download from: Publisher's site
Both athletes and the general population use nutritional supplements. Athletes often turn to supplements hoping that consuming the supplement will help them be more competitive and healthy, while the general population hopes to improve body image or vitality. While many supplements contain ingredients that may have useful properties, there are supplements that are contaminated with compounds that are banned for use in sport or have been deliberately adulterated to fortify a supplement with an ingredient that will produce the advertised effect. In the present study, we have used yeast cell and mammalian cell androgen bioassays to characterize the androgenic bioactivity of 112 sports supplements available from the Australian market, either over the counter or via the Internet. All 112 products did not declare an androgen on the label as an included ingredient. Our findings show that six out of 112 supplements had strong androgenic bioactivity in the yeast cell bioassay, indicating products spiked or contaminated with androgens. The mammalian cell bioassay confirmed the strong androgenic bioactivity of five out of six positive supplements. Supplement 6 was metabolized to weaker androgenic bioactivity in the mammalian cells. Further to this, Supplement 6 was positive in a yeast cell progestin bioassay. Together, these findings highlight that nutritional supplements, taken without medical supervision, could expose or predispose users to the adverse consequences of androgen abuse. The findings reinforce the need to increase awareness of the dangers of nutritional supplements and highlight the challenges that clinicians face in the fast-growing market of nutritional supplements.
Dowse, R, Melvold, J & McGrath, K 2018, 'Students guiding students: Implementing student peer review into a large first year science subject. A Practice Report', Student Success, vol. 9, no. 3, pp. 79-86.View/Download from: Publisher's site
McGrath, KCY, Gangoda, SVS, Li, X-H, McRobb, LS & Heather, AK 2018, 'Inhibitory Effect of a French Maritime Pine Bark Extract-Based Nutritional Supplement on TNF-alpha-Induced Inflammation and Oxidative Stress in Human Coronary Artery Endothelial Cells (vol 2015, 260530, 2015)', EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE.View/Download from: Publisher's site
Saad, S, Al-Odat, I, Chan, YL, McGrath, KC, Pollock, CA, Oliver, BG & Chen, H 2018, 'Maternal L-carnitine supplementation improves glucose and lipid profiles in female offspring of dams exposed to cigarette smoke.', Clinical and experimental pharmacology & physiology, vol. 45, no. 7, pp. 694-703.View/Download from: Publisher's site
Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1β and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.
Chen, H, Li, G, Chan, YL, Chapman, DG, Sukjamnong, S, Nguyen, T, Annissa, T, McGrath, KC, Sharma, P & Oliver, BG 2018, 'Maternal E-Cigarette Exposure in Mice Alters DNA Methylation and Lung Cytokine Expression in Offspring.', American Journal of Respiratory Cell and Molecular Biology, vol. 58, no. 3, pp. 366-377.View/Download from: Publisher's site
E-cigarette usage is increasing, especially among the young, with both the general population and physicians perceiving them as a safe alternative to tobacco smoking. Worryingly, e-cigarettes are commonly used by pregnant women. As nicotine is known to adversely affect children in utero, we hypothesized that nicotine delivered via e-cigarettes would negatively affect lung development. To test this, we developed a mouse model of maternal e-vapor (nicotine and nicotine-free) exposure and investigated the impact on the growth and lung inflammation in both offspring and mothers. Female Balb/c mice were exposed to e-fluid vapor containing nicotine (18 mg/ml nicotine E-cigarette [E-cig18], equivalent to two cigarettes per treatment, twice daily,) or nicotine free (E-cig0 mg/ml) from 6 weeks before mating until pups weaned. Male offspring were studied at Postnatal Day (P) 1, P20, and at 13 weeks. The mothers were studied when the pups weaned. In the mothers' lungs, e-cigarette exposure with and without nicotine increased the proinflammatory cytokines IL-1β, IL-6, and TNF-α. In adult offspring, TNF-α protein levels were increased in both E-cig18 and E-cig0 groups, whereas IL-1β was suppressed. This was accompanied by global changes in DNA methylation. In this study, we found that e-cigarette exposure during pregnancy adversely affected maternal and offspring lung health. As this occurred with both nicotine-free and nicotine-containing e-vapor, the effects are likely due to by-products of vaporization rather than nicotine.
Nguyen, T, Li, GE, Chen, H, Cranfield, CG, McGrath, KC & Gorrie, CA 2018, 'Maternal E-Cigarette Exposure Results in Cognitive and Epigenetic Alterations in Offspring in a Mouse Model.', Chemical research in toxicology, vol. 31, no. 7, pp. 601-611.View/Download from: Publisher's site
Electronic cigarette (e-cigarette) use is on the rise worldwide and is particularly attractive to young people and as a smoking substitute by pregnant woman. There is a perception in pregnant women and women of child-bearing age that the use of e-cigarettes (vaping) is safer than smoking tobacco cigarettes during pregnancy. However, there is little evidence to support this perception. Here, we examined the offspring from mouse dams that had been exposed during and after pregnancy to ambient air (sham) ( n = 8), e-cigarette aerosols with nicotine ( n = 8), or e-cigarette aerosols without nicotine ( n = 8). Offspring underwent cognitive testing at 12 weeks of age and epigenetic testing of brain tissues at 1 day, 20 days, and 13 weeks after birth. The findings showed deficits in short-term memory, reduced anxiety, and hyperactivity in offspring following maternal e-cigarette exposure using the novel object recognition and elevated plus maze tests. In addition, global DNA methylation was increased in the brains of offspring soon after birth. Using a quantitative-PCR array specific to chromatin modification enzymes on genomic DNA and histones,13 key genes were identified to be significantly altered in the offspring brains from the e-cigarette groups compared to the nonexposed groups. The changes to genes Aurka, Aurkb, Aurkc, Kdm5c, Kdm6b, Dnmt3a, Dnmt3b, and Atf2, all associated with modulating neurological activity, were validated using RT-qPCR. In conclusion, in a mouse model, maternal exposure to e-cigarette aerosols resulted in both cognitive and epigenetic changes in offspring. This suggests that the use of e-cigarettes during pregnancy may have hitherto undetected neurological consequences on newborns.
Cooper, ER, McGrath, KC, Li, X, Akram, O, Kasz, R, Kazlauskas, R, McLeod, MD, Handelsman, DJ & Heather, AK 2017, 'The use of tandem yeast and mammalian cell in vitro androgen bioassays to detect androgens in internet-sourced sport supplements.', Drug Testing and Analysis, vol. 9, no. 4, pp. 545-552.View/Download from: Publisher's site
Sport supplements containing steroids never approved for therapeutic use have the potential for abuse by athletes. Most are marketed online and may contain undisclosed steroids yet are readily available despite lacking toxicological or pharmacological evaluation. In this study, 18 supplements purchased online underwent organic solvent extraction to isolate any steroids they contained. From the 18 supplements, 19 steroids were identified and for each, its intrinsic androgenic potency was determined by a yeast cell (Saccharomyces cerevisiae) androgen bioassay and its potential androgenic potency was determined by a liver (HuH7) cell androgen bioassay. The yeast bioassay showed that of the 19 steroids tested, 6 demonstrated strong intrinsic bioactivity, with 4 metabolically activated to even stronger androgens. Moreover, 4 steroids with moderate and 1 with intrinsically weak androgenic bioactivity were activated to more potent androgens. Finally, 8 steroids were metabolically inactivated or deactivated into weaker androgens. Our results show that Internet-sourced sport supplements may contain intrinsically strong androgens, or precursors that can be metabolized to them. These potentially potent pharmacologically active steroids are being used without regulatory control or consumer awareness of their potential adverse effects. Copyright © 2016 John Wiley & Sons, Ltd.
McRobb, LS, McGrath, KCY, Tsatralis, T, Liong, EC, Tan, JTM, Hughes, G, Handelsman, DJ & Heather, AK 2017, 'Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation.', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 6, pp. 1127-1137.View/Download from: Publisher's site
OBJECTIVE: Vascular calcification is associated with increased risk of myocardial infarction and stroke. The objective of this work was to examine the ability of 17β-estradiol (E2) to stimulate calcification of vascular smooth muscle cells (VSMC) in vivo, using aged apolipoprotein E-null mice with advanced atherosclerotic lesions, and subsequently to explore underlying mechanisms in vitro. APPROACH AND RESULTS: Silastic E2 capsules were implanted into male and female apolipoprotein E-null mice aged 34 weeks. Plaque and calcified area were measured in the aortic sinus and innominate artery after 8 weeks. Immunohistochemical analysis examined expression of the estrogen receptors (estrogen receptor alpha and estrogen receptor beta [ERβ]). VSMC expression of osteogenic markers was examined using digital polymerase chain reaction. Advanced atherosclerotic lesions were present in all mice at the end of 8 weeks. In both male and female mice, E2 increased calcified area in a site-specific manner in the aortic sinus independently of plaque growth or lipid levels and occurred in association with a site-specific decrease in the proportion of ERβ-positive intimal cells. Calcified lesions expressed collagen I and bone sialoprotein, with decreased matrix Gla protein. In vitro, E2 suppressed ERβ expression and increased VSMC mineralization, demonstrating increased collagen I and II, osteocalcin and bone sialoprotein, and reduced matrix Gla protein and osteopontin. Antagonism or RNA silencing of estrogen receptor alpha, ERβ, or both further increased VSMC mineralization. CONCLUSIONS: We have demonstrated that E2 can drive calcification in advanced atherosclerotic lesions by promoting the differentiation of VSMC to osteoblast-like cells, a process which is augmented by inhibition of estrogen receptor alpha or ERβ activity.
Cawley, AT, Blakey, K, Waller, CC, Mcleod, MD, Boyd, S, Heather, A, Mcgrath, KC, Handelsman, DJ & Willis, AC 2016, 'Detection and metabolic investigations of a novel designer steroid: 3-chloro-17α-methyl-5α-androstan-17β-ol', Drug Testing and Analysis.View/Download from: Publisher's site
© 2015 John Wiley & Sons, Ltd. In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound; 3-chloro-17α-methyl-5α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new 'designer' steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-5α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-5α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses.
McGrath, KCY, Li, X-H, McRobb, LS & Heather, AK 2015, 'Inhibitory Effect of a French Maritime Pine Bark Extract-Based Nutritional Supplement on TNF-alpha-Induced Inflammation and Oxidative Stress in Human Coronary Artery Endothelial Cells', EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE.View/Download from: Publisher's site
Chan, YL, Saad, S, Simar, D, Oliver, B, McGrath, K, Reyk, DV, Bertrand, PP, Gorrie, C, Pollock, C & Chen, H 2015, 'Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams', International Journal of Developmental Neuroscience, vol. 46, pp. 67-75.View/Download from: Publisher's site
Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.
Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5 μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.
Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.
Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in p...
Cooper, ER, Li, X, McGrath, K & Heather, A 2014, 'Steroidal Extracts from Nutritional Sports Supplements Sold in Australia Test Positive for Androgenic Activity', ENDOCRINE REVIEWS, vol. 35, no. 3.
McGrath, KC, Li, XH, Whitworth, PT, Kasz, R, Tan, JT, McLennan, SV, Celermajer, DS, Barter, PJ, Rye, K-A & Heather, AK 2014, 'High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation', JOURNAL OF LIPID RESEARCH, vol. 55, no. 3, pp. 421-430.View/Download from: Publisher's site
McGrath, KCY, Li, X & Heather, AK 2014, 'Apolipoporotein A-I mimetic peptides improved insulin sensitivity in high fat diet fed mice', Obesity Research & Clinical Practice, vol. 8, pp. 64-65.View/Download from: Publisher's site
Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.
Li, X, McGrath, KC, Tran, VH, Li, Y, Duke, C, Roufogalis, BD & Heather, AK 2013, 'Attenuation of proinflammatory responses by S --Gingerol via inhibition of ROS/NF-Kappa B/COX2 activation in HuH7 cells', Evidenced based Complementary and Alternative Medicine, vol. 2013, pp. 1-8.View/Download from: Publisher's site
Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S--Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor ?B (NF?B) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S--gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1ß to establish an in vitro hepatic inflammatory model. Results. S--Gingerol attenuated IL1ß-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S--gingerol reduced IL1ß-induced COX2 upregulation as well as NF?B activity. Similar to the protective effects of S--gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NF?B inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1ß-induced overexpression of COX2. Of particular note, the protective effect of S--gingerol against the IL1ß-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S--gingerol protects HuH7 cells against IL1ß-induced inflammatory insults through inhibition of the ROS/NF?B/COX2 pathway
Li, X-H, McGrath, KCY, Tran, VH, Li, Y-M, Mandadi, S, Duke, CC, Heather, AK & Roufogalis, BD 2013, 'Identification of a Calcium Signalling Pathway of S--Gingerol in HuH-7 Cells', EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE.View/Download from: Publisher's site
Lim, H, Thiam, C, Yeo, K, Bisoendial, R, Hii, C, McGrath, KC, Tan, K, Heather, AK, Alexander, JR & Angeli, V 2013, 'Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-Mediated transport of HDL', Cell Metabolism, vol. 17, no. 5, pp. 671-684.View/Download from: Publisher's site
Removal of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercho
Li, X, McGrath, KC, Nammi, S, Heather, AK & Roufogalis, BD 2012, 'Attenuation Of Liver Pro-Inflammatory Responses By Zingiber Officinale Via Inhibition Of Nf-Kappa B Activation In High-Fat Diet-Fed Rats', Basic & Clinical Pharmacology & Toxicology, vol. 110, no. 3, pp. 238-244.View/Download from: Publisher's site
The aim of this study was to investigate whether treatment with a ginger (Zingiber officinale) extract of high-fat diet (HFD)-fed rats suppresses Nuclear factor-kappa B (NF-kappa B)-driven hepatic inflammation and to subsequently explore the molecular me
In this issue of Endocrinology, Miani and colleagues (1) provide evidence that increased circulating levels of free fatty acids (FFA) associated with obesity induce a mild endoplasmic reticulum (ER) stress in pancreatic ß-cells that predisposes them to an augmented inflammatory response when exposed to cytokines such as IL-1ß or TNF-a. They found that rat insulinoma cells (INS-1E), or primary rat ß-cells, when exposed to the ER stressor sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) blocker (cyctopiazonic acid) or free fatty acids (FFA), followed by exposure to low-dose IL-1ß or TNF-a, had enhanced expression of the inflammatory markers CCL2, CXCL1, iNOS, and Fas. Interrogation of the molecular pathway showed augmented nuclear factor-?B (NF-?B) activation, after degradation of forkhead box O1 (FoxO1) protein. Using small interfering RNA that targeted specific ER stress pathways, the investigators demonstrated involvement of the inositol-requiring enzyme 1 (IRE1)/X-box binding protein-1s (XBP1s) pathway. The importance of these findings is that obesity-associated FFA may easily induce mild ß-cell ER stress that, in turn, triggers a heightened inflammatory response that could drive apoptosis. ß-cell apoptosis is the primary pathogenic mechanism that underlies type 1 diabetes, an area of growing concern because the worldwide incidence of type 1 diabetes is increasing at a rapid rate.
McGrath, KC, Li, XH, Gaus, K, Williams, P, Celermajer, DS, Handelsman, DJ & Heather, AK 2012, 'Androgens rapidly activate nuclear factor-kappa B via intracellular Ca2+ signalling in human vascular endothelial cells', Journal of Steroids & Hormonal Science, vol. S2, pp. 1-6.
There exists a striking gender difference in the incidence of atherosclerosis. Androgen exposure may predispose men to earlier onset atherosclerosis. We previously demonstrated that the potent androgen, dihydrotestosterone, enhanced the binding of monocytes to endothelial cells, via androgen receptor/nuclear factor kappa B-dependent expression of the cell adhesion molecules, vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1. We now show that testosterone and dihydrotestosterone can also induce a novel, non-genomic pathway that leads to the rapid activation of nuclear factor-kappa B via intracellular Ca2+ signalling, initiated at the plasma membrane. Human umbilical vein endothelial cells exposed to 6-60 nM testosterone or dihydrotestosterone showed a rapid increase in intracellular calcium levels. The testosterone or dihydrotestosterone effect on increased intracellular calcium could not be abrogated by pre-incubation with androgen receptor antagonist, hydroxyflutamide, or by U73122, an inhibitor of intracellular calcium release from endoplasmic reticulum stores.
McGrath, KC, Hill, MD, Mcrobb, L & Heather, AK 2010, 'The androgen receptor drives the sex-specific expression of vascular cell adhesion molecule-1 in endothelial cells but not lipid metabolism genes in monocyte-derived macrophages', Hormone Molecular Biology and Clinical Investigation, vol. 2, no. 1, pp. 203-209.
Background: Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells.Materials and methods: AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis.Results: AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestosterone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-?B-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-?B. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts.
Sieveking, DP, Lim, P, Chow, RW, Dunn, LL, Bao, S, McGrath, KC, Heather, AK, Handelsman, D, Celermajer, DS & Ng, MK 2010, 'A sex-specific role for androgens in angiogenesis', Journal Of Experimental Medicine, vol. 207, no. 2, pp. 345-352.View/Download from: Publisher's site
Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males
McGrath, KC, Li, X, Puranik, R, Liong, E, Tan, J, Dy, V, Dibartolo, B, Barter, P, Rye, K & Heather, AK 2009, 'Role of 3 beta-hydroxysteroid-delta 24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells', Arteriosclerosis Thrombosis And Vascular Biology, vol. 29, no. 6, pp. 877-882.View/Download from: Publisher's site
Objective-The purpose of this study was to investigate the ability of high-density lipoproteins (HDLs) to upregulate genes with the potential to protect against inflammation in endothelial cells. Methods and Results-Human coronary artery endothelial cell
McGrath, KC, Mcrobb, L & Heather, AK 2008, 'Androgen therapy and atherosclerotic cardiovascular disease', Vascular Health and Risk Management, vol. 4, no. 1, pp. 11-21.View/Download from: Publisher's site
Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie
McGrath, KCY, McRobb, LS & Heather, AK 2008, 'Androgen therapy and atherosclerotic cardiovascular disease', Vascular Health and Risk Management, vol. 4, no. 1, pp. 11-21.View/Download from: Publisher's site
Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie. © 2008 Dove Medical Press Limited. All rights reserved.
Skropeta, D, Settasatian, C, McMahon, MR, Shearston, K, Caiazza, D, McGrath, KC, Jin, W, Rader, DJ, Barter, PJ & Rye, K 2007, 'N-Glycosylation regulates endothelial lipase-mediated phospholipid hydrolysis in apoE- and apoA-I-containing high density lipoproteins', Journal of Lipid Research, vol. 48, no. 9, pp. 2047-2057.View/Download from: Publisher's site
Endothelial lipase (EL) is a member of the triglyceride lipase gene family with high phospholipase and low triacylglycerol lipase activities and a distinct preference for hydrolyzing phospholipids in HDL. EL has five potential N-glycosylation sites, four of which are glycosylated. The aim of this study was to determine how glycosylation affects the phospholipase activity of EL in physiologically relevant substrates. Site-directed mutants of EL were generated by replacing asparagine (N) 62, 118, 375, and 473 with alanine (A). These glycan-deficient mutants were used to investigate the kinetics of phospholipid hydrolysis in fully characterized preparations of spherical reconstituted high density lipoprotein (rHDL) containing apolipoprotein E2 (apoE2) [(E2)rHDL], apoE3 [(E3)rHDL], apoE4 [(E4)rHDL], or apoA-I [(A-I)rHDL] as the sole apolipoprotein. Wild-type EL hydrolyzed the phospholipids in (A-I)rHDL, (E2)rHDL, (E3)rHDL, and (E4)rHDL to similar extents. The phospholipase activities of EL N118A, EL N375A, and EL N473A were significantly diminished relative to that of wild-type EL, with the greatest reduction being apparent for (E3)rHDL.
Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a ye
Sader, M, McGrath, KC, Hill, M, Bradstock, K, Jimenez, M, Handelsman, D, Celermajer, DS & Heather, AK 2005, 'Androgen receptor gene expression in leucocytes is hormonally regulated: implications for gender differences in disease pathogenesis', Clinical Endocrinology, vol. 62, no. 1, pp. 56-63.View/Download from: Publisher's site
There is evidence that male sex hormones influence the rate of progression of inflammatory and cardiovascular diseases. We have previously shown that human leucocytes and arterial cells isolated from male donors express more androgen receptor (AR) than t
Wu, T, McGrath, KC & Heather, AK 2005, 'Cardiovascular disease in diabetic nephropathy patients: cell adhesion molecules as potential markers?', Vascular Health and Risk Management, vol. 1, no. 4, pp. 309-316.
Cardiovascular disease is a major complication of diabetes mellitus, especially for patients with diabetic nephropathy. The underlying factor or pathogenic mechanism that links diabetic nephropathy with cardiovascular disease is not known. The endothelial cell adhesion molecules, intercellular adhesion molecule-1 or vascular cell adhesion molecule-1, play a crucial role in the initiation of atherosclerosis. Levels of both cell adhesion molecules are raised by the diabetic and kidney disease states. This review focuses on these important cell adhesion molecules and their role in the pathogenesis of cardiovascular disease in diabetes and diabetic nephropath
Death, AK, McGrath, KC, Sader, MA, Nakhla, S, Jessup, W, Handelsman, DJ & Celermajer, DS 2004, 'Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kB-dependent pathway', Endocrinology, vol. 145, no. 4, pp. 1889-1897.View/Download from: Publisher's site
Heather, AK, McGrath, KC, Kazlauskas, R & Handelsman, D 2004, 'Tetrahydrogestrinone is a potent androgen and progestin', Journal Of Clinical Endocrinology & Metabolism, vol. 89, no. 5, pp. 2498-2500.View/Download from: Publisher's site
Tetrahydrogestrinone (THG) was recently identified as a novel steroid used illicitly to improve athletic performance. Although its structure is closely related to gestrinone, a 19-nor progestin, and resembles that of trenbolone, THG was never marketed, s
Heather, AK, McGrath, KC, Sader, M, Nakhla, S, Jessup, W, Handelsman, D & Celermajer, DS 2004, 'Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappa B-dependent pathway', Endocrinology, vol. 145, no. 4, pp. 1889-1897.View/Download from: Publisher's site
There exists a striking gender difference in atherosclerotic vascular disease. For decades, estrogen was considered atheroprotective; however, an alternative is that androgen exposure in early life may predispose men to earlier atherosclerosis. We recent
Sunde, M, McGrath, KC, Young, L, Matthews, J, Chua, E, Mackay, J & Heather, AK 2004, 'TC-1 is a novel tumorigenic and natively disordered protein associated with thyroid cancer', Cancer Research, vol. 64, no. 8, pp. 2766-2773.View/Download from: Publisher's site
A novel gene, thyroid cancer I (TC-1), was found recently to be overexpressed in thyroid cancer. TC-1 shows no homology to any of the known thyroid cancer-associated genes. We have produced stable transformants of normal thyroid cells that express the TC
Heather, AK, Fisher, E, McGrath, KC & Yue, D 2003, 'High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes', Atherosclerosis, vol. 168, no. 2, pp. 263-269.View/Download from: Publisher's site
Diabetes is a major risk factor for atherosclerosis. Hyperglycemia is an underlying contributing factor; however, the mechanisms that mediate the vascular complications are not yet fully understood. In the present study, we provide evidence that elevated
McGrath, KCY, Sader, MA, Nakhla, S, Handelsman, DJ, Celermajer, DS & Death, AK 2003, 'Androgen exposure increases human monocyte adhesion to vascular endothelium via Up-regulation of VCAM-1 expression in a gender specific manner', Heart, Lung and Circulation, vol. 12, no. 2, pp. A47-A47.View/Download from: Publisher's site
Sader, MA, McGrath, KCY, Handelsman, DJ, Celermajer, DS & Death, AK 2003, 'Leukocyte androgen receptor expression in mice and men; Gender and hormonal regulation, and implications for atherosclerosis', Heart, Lung and Circulation, vol. 12, no. 2, pp. A39-A40.View/Download from: Publisher's site
Heather, AK, Nakhla, S, McGrath, KC, Martell, S, Yue, D, Jessup, W & Celermajer, DS 2002, 'Nitroglycerin upregulates matrix metalloproteinase expression by human macrophages', Journal Of The American College Of Cardiology, vol. 39, no. 12, pp. 1943-1950.View/Download from: Publisher's site
OBJECTIVES This study aimed to determine whether nitroglycerin (NTG) treatment affects matrix metalloproteinase (MMP) gene expression and activities in human macrophages. BACKGROUND Nitroglycerin is one of the most frequently used therapeutic agents for
McGrath, KC & Heather, AK 2012, 'Cardiovascular Disease and Inflammation' in Garg, ML & Wood, LG (eds), Nutrition and Physical Activity in Inflammatory Diseases, CABI, United Kingdom, pp. 1-10.
Stanley, NR, McGrath, KCY, Heather, AK & Hawkins, CL 2010, 'Role of Chlorinated Nucleosides in the Perturbation of Cellular Function under Inflammatory Conditions', FREE RADICAL BIOLOGY AND MEDICINE, 17th Annual Meeting of the Society-for-Free-Radical-Biology-Medicine /15th Biennial Meeting of the Society-for-Free-Radical-Research-International, ELSEVIER SCIENCE INC, Orlando, FL, pp. S130-S130.View/Download from: Publisher's site
Heather, AK, Li, XH, Bartusch, M, Dy, V, Liong, EC, McGrath, KC & Tan, JTM 2009, 'DHCR24 is a negative regulator of NF-B and chronic inflammation in human endothelial cells.', Arteriosclerosis, Thrombosis, and Vascular Biology, You have accessArteriosclerosis, Thrombosis, and Vascular Biology Annual Conference, American Heart Association, pp. E27-E28.View/Download from: Publisher's site
Hill, M, McGrath, KC, Celermajer, DS, Handelsman, DJ & Heather, AK 2008, 'Testosterone has gender-specific effects on atherosclerotic plaque formation mediated by local tissue androgen activation.', Arteriosclerosis, Thrombosis, and Vascular Biology, Arteriosclerosis, Thrombosis, and Vascular Biology Annual Conference, American Heart Association, pp. E83-E83.View/Download from: Publisher's site
Hill, MD, McGrath, KC, Celemajer, DS, Handelsman, DJ & Heather, AK 2007, 'Testosterone has gender-specific effects on atherogenesis', Heart, Lung and Circulation, Elsevier, pp. S164-S164.View/Download from: Publisher's site
Heather, AK, McGrath, KC & Puranik, R 2006, 'HDL exerts novel anti-inflammatory effects on endothelial cells via the suppression of NF-kappaB.', Atherosclerosis Supplements, Elsevier, pp. 232-232.View/Download from: Publisher's site
McGrath, KC, Wu, T & Heather, AK 2006, 'Diabetic nephropathy upregulates endothelial VCAM-1 expression: Potential implications for the high incidence of atherosclerosis.', Atherosclerosis Supplements, Elsevier, pp. 221-221.View/Download from: Publisher's site
Death, A, Lattimore, JDL, McGrath, KCY, Tsatralis, T, Nakhla, S, Wilcox, I & Celermajer, D 2005, 'Repetitive hypoxia decreases matrix metalloproteinase and increases PAI-1 levels in human monocyte derived macrophages', EUROPEAN HEART JOURNAL, 27th Congress of the European-Society-of-Cardiology, OXFORD UNIV PRESS, Stockholm, SWEDEN, pp. 296-296.
McGrath, KCY & Death, A 2005, 'DHT has proatherogenic effects on human endothelial cells via activation of the proinflammatory NFkB by the androgen receptor', EUROPEAN HEART JOURNAL, 27th Congress of the European-Society-of-Cardiology, OXFORD UNIV PRESS, Stockholm, SWEDEN, pp. 542-543.
Death, AK, McGrath, KC, Handelsman, DJ & Celermajer, DS 2004, 'Androgens exert novel genomic and nongenomic effects on human endothelial cells: Implications for the gender differences in atherosclerosis', CIRCULATION, 77th Scientific Meeting of the American-Heart-Association, LIPPINCOTT WILLIAMS & WILKINS, New Orleans, LA, pp. 252-252.