Dr. Chad Weldy is a fellow physician in cardiovascular medicine at Stanford University. He received his M.D. from Duke University School of Medicine and completed his internal medicine internship and residency at Stanford University as a member of the Stanford Translational Investigator Program (TIP). Prior to entering medical school, Dr. Weldy received his Ph.D. from the University of Washington and completed a postdoctoral fellowship with the University of Washington, Division of Cardiology where he conducted basic science research investigations within the fields of cardiovascular biology, redox biology, toxicology, and epigenetics. Dr. Weldy has a clinical interest in the field of inherited cardiomyopathies where he treats patients and families within Stanford’s Center for Inherited Cardiovascular Disease (SCICD) with Dr. Euan Ashley. He is a member of the lab of Dr. Thomas Quertermous where as a physician-scientist he works to better understand human genetics, epigenetics, and transcriptional regulation in cardiovascular disease. He is the recipient of a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (Parent F32) where his grant is titled, "A transcriptional network which governs smooth muscle transition is mediated by causal coronary artery disease gene PDGFD".
- Fellowship - Cardiovascular Medicine
Honors & Awards
AOA - Alpha Omega Alpha Medical Honor Society, Stanford University School of Medicine (6/2020)
2019 Residency Research Travel Award, Stanford University Internal Medicine Residency Program (April, 2019)
2014 Paper of the Year Award, Society of Toxicology, Inhalation and Respiratory Specialty Section (March 24, 2014)
2014 Postdoctoral Travel Award, Society of Toxicology, Cardiovascular Toxicology Specialty Section (March 25, 2014)
1st Place Postdoctoral Presentation Award, Pacific Northwest Association of Toxicologists (September 2013)
2012 Innovations in Research Award, University of Washington Center for Ecogenetics and Environmental Health (CEEH) (May 2012)
Departmental nominee and one of four finalists, University of Washington Graduate School Medal (May 2011)
Young Investigator Award (YIA), Society for Free Radical Biology and Medicine (SFRBM) (November 2011)
1st Place Student/Post Doc Oral Presentation Award, Pacific Northwest Association of Toxicologists (October 2010)
2007 Professor Ming-Ho Yu Award: Outstanding Student in Environmental Toxicology, Huxley College of the Environment, Western Washington University (May 2007)
Cardiovascular Med Fellowship, Stanford University Hospitals, Cardiology (2022)
Internal Medicine Residency, Stanford University Hospitals, Internal Medicine (2019)
Internal Medicine Internship, Stanford University Hospitals, Internal Medicine (2018)
MD, Duke University School of Medicine, Medicine (2017)
Postdoctoral Fellowship, University of Washington, School of Medicine, Division of Cardiology, Cardiovascular Biology, Heart Failure, Epigenetics (2014)
PhD, University of Washington, School of Public Health, Toxicology, Vascular Physiology, Free Radical Biology (2012)
BS, Western Washington University, Huxley College of the Environment, Environmental Toxicology, Chemistry (2007)
Current Research and Scholarly Interests
My long-term goal is to study the complex interaction between human genetic variants, environment, and epigenetic modifiers of transcriptional regulation to inform the discovery of novel treatments for cardiovascular disease.
My research thus far has focused upon understanding how genetics and environment interact to influence redox biology, transcriptional regulation, and epigenetic modifiers of cardiovascular disease. In my PhD work, I made discoveries on how impaired glutathione (GSH) biosynthesis impacts endothelial nitric oxide and vascular tone, and how there is a gene x environment interaction between the GSH synthesis gene Gclm in mediating pulmonary inflammation and systemic vasomotor responses to inhaled diesel exhaust air pollution. In my postdoctoral fellowship work, I made the discovery that in utero exposure to diesel exhaust air pollution increases adult susceptibility to pressure overload induced heart failure in mice using the transverse aortic constriction (TAC) model of heart failure. We further elucidated that this narrow exposure leads to oxidative stress within the placental vascular bed, which subsequently alters adult body weight, blood pressure, and changes global cardiac transcriptional response to TAC. This is mediated in part by altering cardiac DNA methylation profiles which are persistent until adulthood. This work was important to the field as it changed a paradigm by which we understand the effects of air pollution on cardiovascular disease. In addition, during my residency training I have investigated how changes in microRNA expression in circulating cells can reflect dynamic changes in RV function in adult patients with Tetralogy of Fallot, furthering my understanding of non-coding RNA and transcriptional regulation.
Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot.
2020; 15 (11): e0241476
INTRODUCTION: The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure.METHODS: Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent's global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection.RESULTS: MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1alpha signaling was downregulated while p53 signaling was predicted to be upregulated.CONCLUSION: Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.
View details for DOI 10.1371/journal.pone.0241476
View details for PubMedID 33175850
In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation
View details for DOI 10.1096/fj.201700032R
Neonatal Diesel Exhaust Particulate Exposure Does Not Predispose Mice to Adult Cardiac Hypertrophy or Heart Failure
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
2016; 13 (12)
Background: We have previously reported that in utero and early life exposure to diesel exhaust particulates predisposes mice to adult heart failure, and that in utero exposure alone is sufficient to confer this predisposition. This follow up study addresses whether neonatal exposure alone can also confer this predisposition. Methods: Newborn male C57BL/6 mice were exposed to diesel exhaust (DE) particulates immediately after birth until weaning at 21 days of age, whereupon they were transferred to filtered air (FA) conditions. At the age of 12 weeks, transverse aortic constriction (TAC) was performed followed by weekly echocardiography for three weeks. After the last echocardiogram, mice were euthanized for organ harvest, gravimetry and histology. Results: Neonatal exposure to DE particulates did not increase susceptibility to cardiac hypertrophy or heart failure after TAC when compared to FA exposed controls (ventricular weight/body weight ratio 7.505 vs. 7.517 mg/g, p = Not Significant (NS)). The left ventricular ejection fraction after TAC was similar between groups at one week, two weeks, and three weeks after procedure. Histological analysis showed no difference in the degree of cardiac hypertrophy or fibrosis. Conclusions: Neonatal exposure to DE particulates does not predispose mice to TAC-induced cardiac hypertrophy and heart failure in adulthood, in contrast to previously published results showing susceptibility due to in utero exposure.
View details for DOI 10.3390/ijerph13121178
View details for Web of Science ID 000389571900006
View details for PubMedID 27886143
View details for PubMedCentralID PMC5201319
Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias
2014; 28 (7): 3007-3015
CHF1/Hey2 is a Notch-responsive basic helix-loop-helix transcription factor involved in cardiac development. Common variants in Hey2 are associated with Brugada syndrome. We hypothesized that absence of CHF1/Hey2 would result in abnormal cellular electrical activity, altered cardiac conduction system (CCS) development, and increased arrhythmogenesis. We isolated neonatal CHF/Hey2-knockout (KO) cardiac myocytes and measured action potentials and ion channel subunit gene expression. We also crossed myocardial-specific CHF1/Hey2-KO mice with cardiac conduction system LacZ reporter mice and stained for conduction system tissue. We also performed ambulatory ECG monitoring for arrhythmias and heart rate variability. Neonatal cardiomyocytes from CHF1/Hey2-KO mice demonstrate a 50% reduction in action potential dV/dT, a 50-75% reduction in SCN5A, KCNJ2, and CACNA1C ion channel subunit gene expression, and an increase in delayed afterdepolarizations from 0/min to 12/min. CHF1/Hey2 cKO CCS-lacZ mice have a ∼3-fold increase in amount of CCS tissue. Ambulatory ECG monitoring showed no difference in cardiac conduction, arrhythmias, or heart rate variability. Wild-type cells or animals were used in all experiments. CHF1/Hey2 may contribute to Brugada syndrome by influencing the expression of SCN5A and formation of the cardiac conduction system, but its absence does not cause baseline conduction defects or arrhythmias in the adult mouse.-Hartman, M. E., Liu, Y., Zhu, W.-Z., Chien, W.-M., Weldy, C. S., Fishman, G. I., Laflamme, M. A., Chin, M. T. Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias.
View details for DOI 10.1096/fj.14-251728
View details for Web of Science ID 000337949400023
View details for PubMedID 24687990
View details for PubMedCentralID PMC4062830
In Utero Exposure to Diesel Exhaust Air Pollution Promotes Adverse Intrauterine Conditions, Resulting in Weight Gain, Altered Blood Pressure, and Increased Susceptibility to Heart Failure in Adult Mice
2014; 9 (2)
Exposure to fine particulate air pollution (PM₂.₅) is strongly associated with cardiovascular morbidity and mortality. Exposure to PM₂.₅ during pregnancy promotes reduced birthweight, and the associated adverse intrauterine conditions may also promote adult risk of cardiovascular disease. Here, we investigated the potential for in utero exposure to diesel exhaust (DE) air pollution, a major source of urban PM₂.₅, to promote adverse intrauterine conditions and influence adult susceptibility to disease. We exposed pregnant female C57Bl/6J mice to DE (≈300 µg/m³ PM₂.₅, 6 hrs/day, 5 days/week) from embryonic day (E) 0.5 to 17.5. At E17.5 embryos were collected for gravimetric analysis and assessed for evidence of resorption. Placental tissues underwent pathological examination to assess the extent of injury, inflammatory cell infiltration, and oxidative stress. In addition, some dams that were exposed to DE were allowed to give birth to pups and raise offspring in filtered air (FA) conditions. At 10-weeks of age, body weight and blood pressure were measured. At 12-weeks of age, cardiac function was assessed by echocardiography. Susceptibility to pressure overload-induced heart failure was then determined after transverse aortic constriction surgery. We found that in utero exposure to DE increases embryo resorption, and promotes placental hemorrhage, focal necrosis, compaction of labyrinth vascular spaces, inflammatory cell infiltration and oxidative stress. In addition, we observed that in utero DE exposure increased body weight, but counterintuitively reduced blood pressure without any changes in baseline cardiac function in adult male mice. Importantly, we observed these mice to have increased susceptibility to pressure-overload induced heart failure, suggesting this in utero exposure to DE 'reprograms' the heart to a heightened susceptibility to failure. These observations provide important data to suggest that developmental exposure to air pollution may strongly influence adult susceptibility to cardiovascular disease.
View details for DOI 10.1371/journal.pone.0088582
View details for Web of Science ID 000331262600075
View details for PubMedID 24533117
View details for PubMedCentralID PMC3922927
In utero and early life exposure to diesel exhaust air pollution increases adult susceptibility to heart failure in mice
PARTICLE AND FIBRE TOXICOLOGY
Fine particulate air pollution (PM2.5) is a global health concern, as exposure to PM2.5 has consistently been found to be associated with increased cardiovascular morbidity and mortality. Although adult exposure to traffic related PM2.5, which is largely derived from diesel exhaust (DE), has been associated with increased cardiac hypertrophy, there are limited investigations into the potential effect of in utero and early life exposure on adult susceptibility to heart disease. In this study, we investigate the effect of in utero and early life exposure to DE on adult susceptibility to heart failure.Female C57BL/6 J mice were exposed to either filtered air (FA) or DE for 3 weeks (≈ 300 μg/m3 PM2.5 for 6 hours/day, 5 days/week) and then introduced to male breeders for timed matings. Female mice were exposed to either FA or DE throughout pregnancy and until offspring were 3 weeks of age. Offspring were then transferred to either FA or DE for an additional 8 weeks of exposure. At 12 weeks of age, male offspring underwent a baseline echocardiographic assessment, followed by a sham or transverse aortic constriction (TAC) surgery to induce pressure overload. Following sacrifice three weeks post surgery, ventricles were processed for histology to assess myocardial fibrosis and individual cardiomyocyte hypertrophy. mRNA from lung tissue was isolated to measure expression of inflammatory cytokines IL6 and TNFα.We observed that mice exposed to DE during in utero and early life development have significantly increased susceptibility to cardiac hypertrophy, systolic failure, myocardial fibrosis, and pulmonary congestion following TAC surgery compared to FA control, or adult DE exposed mice. In utero and early life DE exposure also strongly modified the inflammatory cytokine response in the adult lung.We conclude that exposure to diesel exhaust air pollution during in utero and early life development in mice increases adult susceptibility to heart failure. The results of this study may imply that the effects of air pollution on cardiovascular disease in human populations may be strongly mediated through a 'fetal origins' of adult disease pathway. Further investigations on this potential pathway of disease are warranted.
View details for DOI 10.1186/1743-8977-10-59
View details for Web of Science ID 000332342800001
View details for PubMedID 24279743
View details for PubMedCentralID PMC3902482
Inhalation of diesel exhaust does not exacerbate cardiac hypertrophy or heart failure in two mouse models of cardiac hypertrophy
PARTICLE AND FIBRE TOXICOLOGY
Strong associations have been observed between exposure to fine ambient particulate matter (PM2.5) and adverse cardiovascular outcomes. In particular, exposure to traffic related PM2.5 has been associated with increases in left ventricular hypertrophy, a strong risk factor for cardiovascular mortality. As much of traffic related PM2.5 is derived from diesel exhaust (DE), we investigated the effects of chronic DE exposure on cardiac hypertrophy and heart failure in the adult mouse by exposing mice to DE combined with either of two mouse models of cardiac hypertrophy: angiotensin II infusion or pressure overload induced by transverse aortic banding.Wild type male C57BL/6 J mice were either infused with angiotensin II (800 ng/kg/min) via osmotic minipump implanted subcutaneously for 1 month, or underwent transverse aortic banding (27 gauge needle 1 week for observing acute reactions, 26 gauge needle 3 months or 6 months for observing chronic reactions). Vehicle (saline) infusion or sham surgery was used as a control. Shortly after surgery, mice were transferred to our exposure facility and randomly assigned to either diesel exhaust (300 or 400 μg/m(3)) or filtered air exposures. After reaching the end of designated time points, echocardiography was performed to measure heart structure and function. Gravimetric analysis was used to measure the ventricular weight to body weight ratio. We also measured heart rate by telemetry using implanted ambulatory ECG monitors.Both angiotensin II and transverse aortic banding promoted cardiac hypertrophy compared to vehicle or sham controls. Transverse aortic banding for six months also promoted heart failure in addition to cardiac hypertrophy. In all cases, DE failed to exacerbate the development of hypertrophy or heart failure when compared to filtered air controls. Prolonged DE exposure also led to a decrease in average heart rate.Up to 6-months of DE exposure had no effect on cardiac hypertrophy and heart function induced by angiotensin II stimulation or pressure overload in adult C57BL/6 J mice. This study highlights the potential importance of particle constituents of ambient PM2.5 to elicit cardiotoxic effects. Further investigations on particle constituents and cardiotoxicity are warranted.
View details for DOI 10.1186/1743-8977-10
View details for Web of Science ID 000325635700001
View details for PubMedID 24093778
View details for PubMedCentralID PMC3851491
Glutathione (GSH) and the GSH synthesis gene Gclm modulate plasma redox and vascular responses to acute diesel exhaust inhalation in mice
2013; 25 (8): 444-454
Inhalation of fine particulate matter (PM₂.₅) is associated with acute pulmonary inflammation and impairments in cardiovascular function. In many regions, PM₂.₅ is largely derived from diesel exhaust (DE), and these pathophysiological effects may be due in part to oxidative stress resulting from DE inhalation. The antioxidant glutathione (GSH) is important in limiting oxidative stress-induced vascular dysfunction. The rate-limiting enzyme in GSH synthesis is glutamate cysteine ligase and polymorphisms in its catalytic and modifier subunits (GCLC and GCLM) have been shown to influence vascular function and risk of myocardial infarction in humans.We hypothesized that compromised de novo synthesis of GSH in Gclm⁻/⁺ mice would result in increased sensitivity to DE-induced lung inflammation and vascular effects.WT and Gclm⁻/⁺ mice were exposed to DE via inhalation (300 μg/m³) for 6 h. Neutrophil influx into the lungs, plasma GSH redox potential, vascular reactivity of aortic rings and aortic nitric oxide (NO•) were measured.DE inhalation resulted in mild bronchoalveolar neutrophil influx in both genotypes. DE-induced effects on plasma GSH oxidation and acetylcholine (ACh)-relaxation of aortic rings were only observed in Gclm⁻/⁺ mice. Contrary to our hypothesis, DE exposure enhanced ACh-induced relaxation of aortic rings in Gclm⁻/⁺ mice.THESE data support the hypothesis that genetic determinants of antioxidant capacity influence the biological effects of acute inhalation of DE. However, the acute effects of DE on the vasculature may be dependent on the location and types of vessels involved. Polymorphisms in GSH synthesis genes are common in humans and further investigations into these potential gene-environment interactions are warranted.
View details for DOI 10.3109/08958378.2013.801004
View details for Web of Science ID 000322067800004
View details for PubMedID 23808636
View details for PubMedCentralID PMC3831526
The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot-Induced Lung Inflammation in Mice
2013; 8 (5)
Quantum dots (QDs) are unique semi-conductor fluorescent nanoparticles with potential uses in a variety of biomedical applications. However, concerns exist regarding their potential toxicity, specifically their capacity to induce oxidative stress and inflammation. In this study we synthesized CdSe/ZnS core/shell QDs with a tri-n-octylphosphine oxide, poly(maleic anhydride-alt-1-tetradecene) (TOPO-PMAT) coating and assessed their effects on lung inflammation in mice. Previously published in vitro data demonstrated these TOPO-PMAT QDs cause oxidative stress resulting in increased expression of antioxidant proteins, including heme oxygenase, and the glutathione (GSH) synthesis enzyme glutamate cysteine ligase (GCL). We therefore investigated the effects of these QDs in vivo in mice deficient in GSH synthesis (Gclm +/- and Gclm -/- mice). When mice were exposed via nasal instillation to a TOPO-PMAT QD dose of 6 µg cadmium (Cd) equivalents/kg body weight, neutrophil counts in bronchoalveolar lavage fluid (BALF) increased in both Gclm wild-type (+/+) and Gclm heterozygous (+/-) mice, whereas Gclm null (-/-) mice exhibited no such increase. Levels of the pro-inflammatory cytokines KC and TNFα increased in BALF from Gclm +/+ and +/- mice, but not from Gclm -/- mice. Analysis of lung Cd levels suggested that QDs were cleared more readily from the lungs of Gclm -/- mice. There was no change in matrix metalloproteinase (MMP) activity in any of the mice. However, there was a decrease in whole lung myeloperoxidase (MPO) content in Gclm -/- mice, regardless of treatment, relative to untreated Gclm +/+ mice. We conclude that in mice TOPO-PMAT QDs have in vivo pro-inflammatory properties, and the inflammatory response is dependent on GSH synthesis status. Because there is a common polymorphism in humans that influences GCLM expression, these findings imply that humans with reduced GSH synthesis capabilities may be more susceptible to the pro-inflammatory effects of QDs.
View details for DOI 10.1371/journal.pone.0064165
View details for Web of Science ID 000319738100020
View details for PubMedID 23724032
View details for PubMedCentralID PMC3664581
Glutathione (GSH) and the GSH synthesis gene Gclm modulate vascular reactivity in mice
FREE RADICAL BIOLOGY AND MEDICINE
2012; 53 (6): 1264-1278
Oxidative stress has been implicated in the development of vascular disease and in the promotion of endothelial dysfunction via the reduction in bioavailable nitric oxide (NO()). Glutathione (GSH) is a tripeptide thiol antioxidant that is utilized by glutathione peroxidase (GPx) to scavenge reactive oxygen species such as hydrogen peroxide and phospholipid hydroperoxides. Relatively frequent single-nucleotide polymorphisms (SNPs) within the 5' promoters of the GSH synthesis genes GCLC and GCLM are associated with impaired vasomotor function, as measured by decreased acetylcholine-stimulated coronary artery dilation, and with increased risk of myocardial infarction. Although the influence of genetic knockdown of GPx on vascular function has been investigated in mice, no work to date has been published on the role of genetic knockdown of GSH synthesis genes on vascular reactivity. We therefore investigated the effects of targeted disruption of Gclm in mice and the subsequent depletion of GSH on vascular reactivity, NO() production, aortic nitrotyrosine protein modification, and whole-genome transcriptional responses as measured by DNA microarray. Gclm(-/+) and Gclm(-/-) mice had 72 and 12%, respectively, of wild-type (WT) aortic GSH content. Gclm(-/+) mice had a significant impairment in acetylcholine (ACh)-induced relaxation in aortic rings as well as increased aortic nitrotyrosine protein modification. Surprisingly, Gclm(-/-) aortas showed enhanced relaxation compared to Gclm(-/+) aortas, as well as increased NO() production. Although aortic rings from Gclm(-/-) mice had enhanced ACh relaxation, they had a significantly increased sensitivity to phenylephrine (PE)-induced contraction. Alternatively, the PE response of Gclm(-/+) aortas was nearly identical to that of their WT littermates. To examine the role of NO() or other potential endothelium-derived factors in differentially regulating vasomotor activity, we incubated aortic rings with the NO() synthase inhibitor L-NAME or physically removed the endothelium before PE treatment. L-NAME treatment and endothelium removal enhanced PE-induced contraction in WT and Gclm(-/+) mice, but this effect was severely diminished in Gclm(-/-) mice, indicating a potentially unique role for GSH in mediating vessel contraction. Whole-genome assessment of aortic mRNA in Gclm(-/-) and WT mice revealed altered expression of genes within the canonical Ca(2+) signaling pathway, which may have a role in mediating these observed functional effects. These findings provide additional evidence that the de novo synthesis of GSH can influence vascular reactivity and provide insights regarding possible mechanisms by which SNPs within GCLM and GCLC influence the risk of developing vascular diseases in humans.
View details for DOI 10.1016/j.freeradbiomed.2012.07.006
View details for Web of Science ID 000308903800006
View details for PubMedID 22824862
View details for PubMedCentralID PMC3625031
DIESEL particulate exposed macrophages alter endothelial cell expression of eNOS, iNOS, MCP1, and glutathione synthesis genes
TOXICOLOGY IN VITRO
2011; 25 (8): 2064-2073
There is considerable debate regarding inhaled diesel exhaust particulate (DEP) causing impairments in vascular reactivity. Although there is evidence that inhaled particles can translocate from the lung into the systemic circulation, it has been suggested that inflammatory factors produced in the lung following macrophage particle engulfment also pass into the circulation. To investigate these differing hypotheses, we used in vitro systems to model each exposure. By using a direct exposure system and a macrophage-endothelial cell co-culture model, we compared the effects of direct DEP exposure and exposure to inflammatory factors produced by DEP-treated macrophages, on endothelial cell mRNA levels for eNOS, iNOS, endothelin-1, and endothelin-converting-enzyme-1. As markers of oxidative stress, we measured the effects of DEP treatment on glutathione (GSH) synthesis genes and on total GSH. In addition, we analyzed the effect of DEP treatment on monocyte chemo-attractant protein-1. Direct DEP exposure increased endothelial GCLC and GCLM as well as total GSH in addition to increased eNOS, iNOS, and Mcp1 mRNA. Alternatively, inflammatory factors released from DEP-exposed macrophages markedly up-regulated endothelial iNOS and Mcp1 while modestly down-regulating eNOS. These data support both direct exposure to DEP and the release of inflammatory cytokines as explanations for DEP-induced impairments in vascular reactivity.
View details for DOI 10.1016/j.tiv.2011.08.008
View details for Web of Science ID 000298362500070
View details for PubMedID 21920430
View details for PubMedCentralID PMC3217165
Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice
2011; 23 (12): 724-735
Inhalation of ambient fine particulate matter (PM₂.₅) is associated with adverse respiratory and cardiovascular effects. A major fraction of PM₂.₅ in urban settings is diesel exhaust particulate (DEP), and DEP-induced lung inflammation is likely a critical event mediating many of its adverse health effects. Oxidative stress has been proposed to be an important factor in PM₂.₅-induced lung inflammation, and the balance between pro- and antioxidants is an important regulator of this inflammation. An important intracellular antioxidant is the tripeptide thiol glutathione (GSH). Glutamate cysteine ligase (GCL) carries out the first step in GSH synthesis. In humans, relatively common genetic polymorphisms in both the catalytic (Gclc) and modifier (Gclm) subunits of GCL have been associated with increased risk for lung and cardiovascular diseases.This study was aimed to determine the effects of Gclm expression on lung inflammation following DEP exposure in mice.We exposed Gclm wild type, heterozygous, and null mice to DEP via intranasal instillation and assessed lung inflammation as determined by neutrophils and inflammatory cytokines in lung lavage, inflammatory cytokine mRNA levels in lung tissue, as well as total lung GSH, Gclc, and Gclm protein levels.The Gclm heterozygosity was associated with a significant increase in DEP-induced lung inflammation when compared to that of wild type mice.This finding indicates that GSH synthesis can mediate DEP-induced lung inflammation and suggests that polymorphisms in Gclm may be an important factor in determining adverse health outcomes in humans following inhalation of PM₂.₅.
View details for DOI 10.3109/08958378.2011.608095
View details for Web of Science ID 000295478800004
View details for PubMedID 21967497
View details for PubMedCentralID PMC3337699