Colin Murdoch

Verified

Colin verified their affiliation via an institutional email.

Learn more

Verified

Colin verified their affiliation via an institutional email.

Learn more

• Ph.D
• Reader at University of Dundee

Objectives To investigate the effect of endothelial dysfunction on development of cardiac hypertrophy and fibrosis. Background Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis but its contribution to these conditions is unclear. Increased NADPH oxidase-2 (NOX2) activation causes endothelial dysfunction. Methods Transgenic mice...

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes. Glrx overexpression inhibits VEGF-induced endothelial cell (EC) migration. The aim was to inve...

S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflamma...

Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the...

NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-...

Background: In cardiac dysfunction, intracellular Ca2+-dynamics are disrupted leading to leakage of Ca2+ from the sarcoplasmic reticulum (SR). This results in diminished cardiac contractility and impaired cardiac function. In cardiac tissue, the underlying molecular mechanisms responsible for RyR2-independent Ca2+ leak are poorly understood. Mitsug...

Obesity-related glomerulopathy (ORG) contributes to diabetic nephropathy and kidney cancer, leading to chronic/end-stage kidney disease. To date, treatments for ORG are limited because of incomplete understanding of the disease pathogenesis. Here, we identified a novel role for hyaluronan (HA) and its membrane receptors, CD44 and RHAMM in obesity-a...

Objective Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is imperative to determine whether the increased ECM deposition contributes to this disease cluster. The hypotheses tested in this study were that in cardiac tissue of obese mice i...

The placenta is a unique cardiovascular organ that receives blood supplies from both the maternal and the fetal system. Dysfunction of the placenta can lead to gestational hypertension and lifelong cardiovascular consequences for both mother and baby. Yet our ability to study placenta dysfunction often relies on sourcing trophoblasts from either te...

Background Preeclampsia is a severe pregnancy complication which has long-term consequences on mother and child. Elevation of the soluble isoform of the anti-angiogenic factor sFlt1 in the maternal circulation is pivotal in the development of gestational hypertension, and kidney and placental dysfunction. Hallmarks of preeclampsia include oxidative...

Hallmarks of obesity Western diets, include increased cardiac oxidative stress and cardiovascular diseases (CVDs) and are characterised by a high fat/high sucrose (HFHS) content. In CVD, oxidative post-translational modifications (oxPTM) like S-glutathionylation are known to play important roles. Glutaredoxin-1 (Grx1) which reverses S-glutathionyla...

Introduction Preeclampsia is a major cause of maternal morbidity and mortality. The dangers are not limited to gestational complications; a single preeclampsia episode predisposes to many serious future health conditions. Little is known about how preeclampsia impacts the onset and clinical course of type 2 diabetes (T2D). Methods The Scottish Car...

Jagged1 has essential roles in cardiovascular development and maintenance by regulating angiogenesis, which is tightly controlled by redox signalling in endothelial cells (EC). Proteins sense redox signals through certain cysteine residues forming oxidative post translational modifications (ox-PTM) which alter protein function. Iodoacetyl-tandem ma...

Extracellular matrix (ECM) remodelling has recently emerged as an important contributor to insulin resistance. Systemic insulin resistance is associated with abnormalities in cardiac function. However, the role of cardiac ECM remodelling and insulin resistance in cardiac dysfunction is poorly documented. Our previous studies showed that inhibiting...

In the failing heart, Ca²⁺-cycling is profoundly altered, leading to leak of Ca²⁺ from the sarcoplasmic reticulum (SR)¹. This results in impaired cardiac contraction and arrhythmias. The underlying molecular mechanisms governing SR Ca²⁺ leak are unclear.Mitsugumin 23 (MG23) is a Ca²⁺-conducting ion channel located on ER/SR and nuclear membranes². T...

Organ-on-a-chip technology incorporating stem cell techniques represents a promising strategy to improve modeling of human organs. Here, we present a protocol for generating a standardized 3D placenta-on-a-chip model using trophoblast derived from human induced pluripotent stem cells (hiPSCs). We describe steps for seeding hiPSCs into multi-chip Or...

Laser speckle contrast imaging (LSCI) is an important non-invasive capability for real-time imaging for tissue-perfusion assessment. Yet, the size and weight of current clinical standard LSCI instrumentation restricts usage to mainly peripheral skin perfusion. Miniaturization of LSCI could enable hand-held instrumentation to image internal organ/ti...

Increased deposition of extracellular matrix (ECM) components such as collagens and hyaluronan contributes to the pathogenesis of obesity-associated insulin resistance in muscle, liver, and adipose tissue. Despite the significance of the heart in cardiovascular and metabolic diseases, maladaptive ECM remodelling in obesity-associated cardiac insuli...

Objective: The maternal cardiovascular system of women with hypertensive disorders of pregnancy (HDP) can be impaired, with higher rates of left ventricular (LV) remodelling and diastolic dysfunction compared to normotensive pregnancies. The primary objective of this prospective study was to correlate cardiac indices obtained by transthoracic echo...

Although recently developed placenta-on-chip systems opened promising perspectives for placental barrier modeling, they still lack physiologically relevant trophoblasts and are poorly amenable to high-throughput studies. We aimed to implement human-induced pluripotent stem cells (hiPSC)-derived trophoblasts into a multi-well microfluidic device to...

Pathologies associated with uteroplacental hypoxia, such as preeclampsia are among the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and end...

Jagged1 (Jag1) has essential roles in angiogenesis and development. Altered function of this transmembrane protein results in congenital birth defects and cancer progression. Redox signalling regulates cardiovascular physiology through Endothelial cells (EC). Proteins sense redox signals through cysteine thiols. Free radicals react with redox sensi...

Western diets, characterised by a high fat/high sucrose (HFHS) content, are associated with increased cardiac oxidative stress and cardiovascular diseases (CVDs). Increased post-translational modifications (oxPTM) like S-glutathionylation are correlated with the aetiology of CVD. Glutaredoxin-1 (Grx1) reverses S-glutathionylation and is overexpress...

Angiotensin-II (AngII) induces hypertension and cardiac hypertrophy and is a potent inductor of oxidative stress, which causes oxidative post-translational modifications (oxPTM). Glutaredoxin-1 (Glrx) catalyses the removal of an oxPTM, S-glutathionylation, and has been shown to be important in peripheral artery disease. Thereorfore, we investigated...

Elevation of oxidative stress is explicitly linked to hypertensive pregnancies with high levels measurable in the maternal circulation. Hypertensive pregnancies lead to life-long risk of cardiac dysfunction, yet the underpinning molecular pathway are unknown. Oxidative stress modify proteins via oxidative post-translational modifications (ox-PTMs)...

In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samp...

Reactive oxygen species (ROS) have different properties and biological functions. They contribute to cell signaling and, in excessive amounts, to oxidative stress (OS). Although ROS is pivotal in a wide number of physiological systems and pathophysiological processes, direct quantification in vivo is quite challenging and mainly limited to in vitro...

Preeclampsia is one of the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and endothelial cells against a collagen extracellular matrix in a...

Human pregnancy can be affected by numerous pathologies, from those which are mild and reversible to others which are life-threatening. Among these, gestational diabetes mellitus and hypertensive disorders of pregnancy with subsequent consequences stand out. Health problems experienced by women during pregnancy and postpartum are associated with si...

Women affected by hypertensive disorders of pregnancy and fetal growth restriction frequently present alterations in the cardiovascular system, even before the clinical onset of the pathology. The objective of this study is to assess the relationship between peripheral vascular system (ophthalmic and uterine arteries), cardiac output and adverse fe...

Background Elevation of circulating anti-angiogenic factors is pivotal in the development of the preeclampsia (PE) phenotype of incomplete vascular remodelling, hypertension and kidney dysfunction during pregnancy. Oxidative stress is explicitly linked to PE with high levels measurable in the placenta. Yet antioxidant therapy has failed, in some ca...

Redox signalling plays an important role in endothelial cell (EC) physiology and pathophysiology. Proteins sense redox signals via cysteine thiol groups. A common oxidative post-translational modification (oxPTM) on cysteine thiols is S-glutathionylation which is reversed to a free thiol state by glutaredoxin (Glrx). OxPTMs alter protein function,...

Practical demonstration of cardiomyocyte function requires substantial preparation, a source of freshly isolated animal hearts and specialized equipment. Even where such resources are available, it is not conducive for demonstration to any more than a few students at a time. These approaches are also not consistent with the 3R principle (replacemen...

Aims: Endothelial activation and inflammatory cell infiltration have important roles in the development of cardiac fibrosis induced by renin-angiotensin system activation. NADPH oxidases (Nox proteins) are expressed in endothelial cells (ECs) and alter their function. Previous studies indicated that Nox2 in ECs contributes to angiotensin II (AngII...

Background Elevation of the anti-angiogenic factor soluble Flt-1 (sFlt-1) is pivotal in the development of the preeclampsia phenotype of hypertension and kidney dysfunction during pregnancy. Likewise, oxidative stress is explicitly linked to preeclampsia with high levels measurable both in the placenta and maternal circulation. Yet antioxidant ther...

Glutaredoxin‐1 (Glrx) is a small cytosolic enzyme that removes S‐glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription. Although Glrx up‐regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell...

Oxidative post-translational modifications (oxPTM) of receptors, enzymes, ion channels and transcription factors play an important role in cell signaling. oxPTMs are a key way in which oxidative stress can influence cell behavior during diverse pathological settings such as cardiovascular diseases (CVD), cancer, neurodegeneration and inflammatory r...

Interleukin (IL)-33 is an interleukin-1 like cytokine that enhances Th2 responses and mediates mucosal immunity and allergic inflammation but the mechanism regulating endogenous IL-33 production are still under investigation. In macrophages, lipopolysaccharide (LPS) administration resulted in marked induction of IL-33 mRNA that was blunted in macro...

CRA-induced IL-33 in RAW cells. Different doses of CRA (0–80 μg/ml) was tested to examine IL-33 and Glrx induction in RAW cells with siControl or siGlrx RNA. (PDF)

F4/80 staining on mouse peritoneal macrophages. Adhered peritoneal cells were fixed and stained with anti-mouse F4/80 antibody (red) and Hoechst (blue). (PDF)

CRA-induced Glrx mRNA in WT and IL-33 KO mouse macrophages. CRA (Cockroach antigen 100 μg/ml) or PBS was added in isolated mouse macrophages from WT and IL-33 KO mice. After 6 hours RNA was isolated from cells by Trizol and Glrx expression was examined (n = 3–4 wells). (PDF)

IL-33-induced IL-33 protein is shifted in non-reduced condition. LPS (100ng/ml) or IL-33 (50 ng/ml) was added in RAW cells for 6 hours, and cellular proteins were analyzed in reduced and non-reduced gel. (PDF)

Cardiac fibrosis is implicit in all forms of heart disease but there are no effective treatments. In this report, we investigate the role of the multi-functional enzyme Transglutaminase 2 (TG2) in cardiac fibrosis and assess its potential as a therapeutic target. Here we describe the use a highly selective TG2 small-molecule inhibitor to test the e...

Ischemic heart disease (IHD) is one of the primary causes of death around the world. Therapeutic angiogenesis is a promising innovative approach for treating IHD, improving cardiac function by promoting blood perfusion to the ischemic myocardium. This treatment is especially important for targeting patients that are unable to undergo angioplasty or...

Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical...

Mechanisms for the lack of efficacy of anti-angiogenic strategies for cancer have not been elucidated. We previously demonstrated that up-regulated glutaredoxin-1 (Glrx) inhibited endothelial cell (EC) angiogenic properties. Glrx is a small cytosolic enzyme which reverses glutathione adducts on protein thiols. Global Glrx transgenic mice had impair...

Introduction High soluble Flt1 (sFlt1) is pivotal in the development of ‘preeclampsia phenotype’ of hypertension and proteinuria. Disruption of endogenous protective pathways and increased oxidative stress are hallmarks.of preeclampsia. Yet the underlying molecular mechanisms remains unclear. During high oxidative stress, thiols on key proteins are...

Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions. When their balance is shifted towards enhanced amounts of free radicals, pathological phenomena can occur, as the generation of reactive oxygen species (ROS) in tissue microenvironment or in the systemic circulation can be detrimental...

Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice...

Background Hypertension caused by increased renin-angiotensin system activation is associated with elevated reactive oxygen species production. Previous studies implicate NADPH oxidase (Nox) proteins as important reactive oxygen species sources during renin-angiotensin system activation, with different Nox isoforms being potentially involved. Among...

Vascular endothelial growth factor (VEGF) signaling is tightly regulated by specific VEGF receptors (VEGF-R). Recently, we identified heterodimerisation between VEGFR-1 and VEGFR-2 (VEGFR1–2) to regulate VEGFR-2 function. However, both the mechanism of action and the relationship with VEGFR-1 homodimers remain unknown. The current study shows that...

Background: Increased reactive oxygen species (ROS) production is involved in the process of adverse cardiac remodeling and development of heart failure after myocardial infarction (MI). NADPH oxidase-2 (Nox2) is a major ROS source within the heart and its activity increases after MI. Furthermore, genetic deletion of Nox2 is protective against pos...

Significance Glutathione (GSH)-protein adducts are oxidative posttranslational modifications that are reversed by glutaredoxin-1 (Glrx). We show that ischemia-induced oxidants promote revascularization through GSH adducts on hypoxia-inducible factor (HIF)-1α, an angiogenic transcriptional factor. GSH adducts on Cys ⁵²⁰ stabilize HIF-1α protein, and...

The endothelium produces and responds to reactive oxygen and nitrogen species (RONS), providing important redox regulation to the cardiovascular system in physiology and disease. In no other situation are RONS more critical than in the response to tissue ischemia. Here, tissue healing requires growth factor-mediated angiogenesis that is in part dep...

Potent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled...

INTRODUCTION: Preeclampsia is a vascular disorder in pregnancy and is biochemical characterization by high soluble Flt-1 and low placenta growth factor as well as an imbalance in redox homeostasis. During conditions of high oxidative stress, cysteine residues on key proteins are reversibly altered by S-glutathionylation, modifying their function....

Reactive oxygen species (ROS) are increased during ischemia, but decreasing ROS in endothelial cells impairs revascularization. Low levels of ROS regulate protein function by inducing S-glutathionylation, a reversible post-translational protein modification that may change protein(s) function directly. Protein S-glutathionylation is increased in ox...

Myocardial infarction results in loss of cardiac muscle and deficiency in cardiac performance. Likewise, peripheral artery disease can result in critical limb ischemia leading to reduced mobility, non-healing ulcers, gangrene and amputation. Both of these common conditions diminish quality of life and enhance risk of mortality. Successful advances...

Mesenchymal stem cells (MSCs) represent a promising cell population for cell therapy and regenerative medicine applications. However, how variations in glucose are perceived by MSC pool is still unclear. Since, glucose metabolism is cell type and tissue dependent, this must be considered when MSCs are derived from alternative sources such as the he...

Figure 2: C-MSC basal growth rate was evaluated by seeding the cells in IMDM/10% FBS in 12-well plates (6.000 cells/cm2). The number of viable cells was obtained by performing a Trypan Blue exclusion assay at 24 and 48 hours.

-The molecular mechanisms underlying similarities and differences between physiological and pathological left ventricular hypertrophy (LVH) are of intense interest. Most previous work involved targeted analysis of individual signaling pathways or screening of transcriptomic profiles. We developed a network biology approach using genomic and proteom...

Glutaredoxin‐1 (Glrx) catalyzes the reduction of protein mixed disulfides (PSSG) and regulates function of proteins with redox‐sensitive thiols. We used Glrx transgenic (Tg) mice to investigate the role of Glrx overexpression on angiogenesis in vivo. Tg mice had impaired blood flow recovery and lower clinical function scores in an in vivo model of...

Alternative splicing of the gene encoding vascular endothelial growth factor receptor 1(VEGFR1/FLT1) generates an anti‐angiogenic soluble form (sVEGFR1/sFLT). sVEGFR1 has a high affinity for VEGF‐A and can act as a decoy receptor, preventing signaling through the pro‐angiogenic VEGFR2 receptor. Regulation of sVEGFR1 expression in endothelial cells...

IntroductionMice globally deficient in Nox2 are protected against cardiac fibrosis in response to chronic AngII infusion even though the degree of hypertrophy was unaltered. The selective effect of Nox2 on fibrosis may reflect its activation in a non-cardiomyocyte cell type. We hypothesised that Nox2, which is expressed in endothelial cells and inf...

Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H(2)O(2)), but its role in viv...