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Publication Record


Cardiovascular Disease Risk Factors in Ghana during the Rural-to-Urban Transition: A Cross-Sectional Study.
Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Poku KA, Brown NJ, Moore JH, Williams SM
(2016) PLoS One 11: e0162753
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Ghana, Humans, Hypertension, Male, Middle Aged, Obesity, Plasminogen Activator Inhibitor 1, Prevalence, Risk Factors, Smoking, Surveys and Questionnaires, Tissue Plasminogen Activator, Triglycerides, Urbanization, Young Adult
Show Abstract · Added April 6, 2017
Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ~250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3-11.3), diabetes (OR 3.6, 95% CI: 2.3-5.7), and hypertension (OR 3.2, 95% CI: 2.6-4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73-0.88), LDL cholesterol (+0.89, 95% CI: 0.79-0.99), and t-PA (+0.56, 95% CI: 0.48-0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.
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29 MeSH Terms
Plasminogen Activator Inhibitor-1 and Diagnosis of the Metabolic Syndrome in a West African Population.
Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, Williams SM
(2016) J Am Heart Assoc 5:
MeSH Terms: Adolescent, Adult, Antihypertensive Agents, Blood Glucose, Blood Pressure, Body Mass Index, Cholesterol, HDL, Cross-Sectional Studies, Diabetes Mellitus, Fasting, Female, Ghana, Humans, Hypertension, Hypoglycemic Agents, Male, Metabolic Syndrome, Middle Aged, Plasminogen Activator Inhibitor 1, Prevalence, Rural Population, Triglycerides, Urban Population, Young Adult
Show Abstract · Added April 6, 2017
BACKGROUND - Metabolic syndrome (MetS) is diagnosed by the presence of at least 3 of the following: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein. Individuals with MetS also typically have elevated plasma levels of the antifibrinolytic factor, plasminogen activator inhibitor-1 (PAI-1), but the relationships between PAI-1 and MetS diagnostic criteria are not clear. Understanding these relationships can elucidate the relevance of MetS to cardiovascular disease risk, because PAI-1 is associated with ischemic events and directly involved in thrombosis.
METHODS AND RESULTS - In a cross-sectional analysis of 2220 Ghanaian men and women from urban and rural locales, we found the age-standardized prevalence of MetS to be as high as 21.4% (urban women). PAI-1 level increased exponentially as the number of diagnostic criteria increased linearly (P<10), supporting the conclusion that MetS components have a joint effect that is stronger than their additive contributions. Body mass index, triglycerides, and fasting glucose were more strongly correlated with PAI-1 than with canonical MetS criteria, and this pattern did not change when pair-wise correlations were conditioned on all other risk factors, supporting an independent role for PAI-1 in MetS. Finally, whereas the correlations between conventional risk factors did not vary significantly by sex or across urban and rural environments, correlations with PAI-1 were generally stronger among urban participants.
CONCLUSIONS - MetS prevalence in the West African population we studied was comparable to that of the industrialized West. PAI-1 may serve as a key link between MetS, as currently defined, and the endpoints with which it is associated. Whether this association is generalizable will require follow-up.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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24 MeSH Terms
Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial.
Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA
(2015) J Clin Endocrinol Metab 100: 4533-40
MeSH Terms: Adult, Albuminuria, Double-Blind Method, Endothelium, Vascular, Female, Fibrinolysis, Glucose, Glucose Clamp Technique, Glucose Tolerance Test, Hemodynamics, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Overweight, Phosphodiesterase 5 Inhibitors, Plasminogen Activator Inhibitor 1, Prediabetic State, Sildenafil Citrate
Show Abstract · Added November 30, 2015
CONTEXT - Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.
OBJECTIVE - The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.
DESIGN - This was a randomized, double-blind, placebo-controlled study.
SETTING - This trial was conducted at Vanderbilt Clinical Research Center.
PARTICIPANTS - Participants included overweight individuals with prediabetes.
INTERVENTIONS - Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.
MAIN OUTCOME MEASURES - The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.
RESULT - Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.
CONCLUSIONS - Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.
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20 MeSH Terms
Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.
White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, Moore JH, Williams SM
(2015) PLoS One 10: e0136379
MeSH Terms: Adult, Cardiovascular Diseases, Circadian Rhythm, European Continental Ancestry Group, Female, Ghana, Humans, Male, N-Acetylgalactosamine-4-Sulfatase, Period Circadian Proteins, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide
Show Abstract · Added April 6, 2017
Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).
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12 MeSH Terms
Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
Samarakoon R, Helo S, Dobberfuhl AD, Khakoo NS, Falke L, Overstreet JM, Goldschmeding R, Higgins PJ
(2015) J Pathol 236: 421-32
MeSH Terms: Animals, Apoptosis, Aristolochic Acids, Cell Cycle Checkpoints, Cell Line, Cell Proliferation, Disease Models, Animal, Enzyme Inhibitors, Fibrosis, Gene Expression Regulation, Humans, Kidney Diseases, Kidney Tubules, Male, Mice, Inbred C57BL, PTEN Phosphohydrolase, Plasminogen Activator Inhibitor 1, RNA Interference, Signal Transduction, Smad3 Protein, Streptozocin, Transfection, Transforming Growth Factor beta1, Tumor Suppressor Protein p53, Ureteral Obstruction
Show Abstract · Added April 19, 2016
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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25 MeSH Terms
Redox control of p53 in the transcriptional regulation of TGF-β1 target genes through SMAD cooperativity.
Overstreet JM, Samarakoon R, Meldrum KK, Higgins PJ
(2014) Cell Signal 26: 1427-36
MeSH Terms: Acetylation, Animals, Cell Line, DNA-Binding Proteins, Enzyme Activation, Epithelial Cells, Fibroblasts, Fibrosis, Gene Expression Regulation, Humans, Keratinocytes, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, NADPH Oxidases, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta1, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
Transforming growth factor-β1 (TGF-β1) regulates the tissue response to injury and is the principal driver of excessive scarring leading to fibrosis and eventual organ failure. The TGF-β1 effectors SMAD3 and p53 are major contributors to disease progression. While SMAD3 is an established pro-fibrotic factor, the role of p53 in the TGF-β1-induced fibrotic program is not clear. p53 gene silencing, genetic ablation/subsequent rescue, and pharmacological inhibition confirmed that p53 was required for expression of plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1 target gene and a key causative element in fibrotic disorders. TGF-β1 regulated p53 activity by stimulating p53(Ser15 and 9) phosphorylation and acetylation, promoting interactions with activated SMADs and subsequent binding of p53/SMAD3 to the PAI-1 promoter in HK-2 human renal tubular epithelial cells and HaCaT human keratinocytes. Immunohistochemistry revealed prominent co-induction of SMAD3, p53 and PAI-1 in the tubular epithelium of the obstructed kidney consistent with a potential in vivo role for p53 and SMADs in TGF-β1-driven renal fibrosis. TGF-β1-initiated phosphorylation of p53(Ser15) and up-regulation of expression of several pro-fibrotic genes, moreover, was dependent on the rapid generation of reactive oxygen species (ROS). shRNA silencing of the p22(Phox) subunit of NADP(H) oxidases in HK-2 cells partially attenuated (over 50%) p53(Ser15) phosphorylation and PAI-1 induction. These studies highlight the role of free radicals in p53 activation and subsequent pro-fibrotic reprogramming by TGF-β1 via the SMAD3-p53 transcriptional axis. Present findings provide a rationale for therapeutic targeting of SMAD3-p53 in aberrant TGF-β1 signaling associated with renal fibrosis.
Copyright © 2014 Elsevier Inc. All rights reserved.
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27 MeSH Terms
Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.
Bagai K, Muldowney JA, Song Y, Wang L, Bagai J, Artibee KJ, Vaughan DE, Malow BA
(2014) Sleep 37: 359-67
MeSH Terms: Biomarkers, Body Mass Index, Cardiovascular Diseases, Case-Control Studies, Circadian Rhythm, Cross-Sectional Studies, Endothelial Cells, Female, Humans, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Polysomnography, Sleep, Sleep Apnea, Obstructive, Tissue Plasminogen Activator
Show Abstract · Added March 10, 2014
STUDY OBJECTIVES - Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls.
SETTING - Cross-sectional cohort study.
PATIENTS OR PARTICIPANTS - Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA.
INTERVENTIONS - Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis.
MEASUREMENTS AND RESULTS - The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups.
CONCLUSION - The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.
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2 Members
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16 MeSH Terms
Association of soy food intake with risk and biomarkers of coronary heart disease in Chinese men.
Yu D, Zhang X, Xiang YB, Yang G, Li H, Fazio S, Linton M, Cai Q, Zheng W, Gao YT, Shu XO
(2014) Int J Cardiol 172: e285-7
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Biomarkers, Cohort Studies, Coronary Disease, Cross-Sectional Studies, Eating, Follow-Up Studies, Humans, Interleukin-8, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Prospective Studies, Risk Factors, Soy Foods
Added March 18, 2014
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17 MeSH Terms
A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1.
Hamasaki Y, Doi K, Maeda-Mamiya R, Ogasawara E, Katagiri D, Tanaka T, Yamamoto T, Sugaya T, Nangaku M, Noiri E
(2013) Am J Physiol Renal Physiol 305: F1796-803
MeSH Terms: Adenine, Animals, Cells, Cultured, Disease Models, Animal, Fatty Acid-Binding Proteins, Fibrosis, In Vitro Techniques, Kidney Tubules, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nephritis, Interstitial, Plasminogen Activator Inhibitor 1, Regional Blood Flow, Serotonin, Serotonin Antagonists, Succinates, Transforming Growth Factor beta1, Up-Regulation
Show Abstract · Added February 11, 2016
A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells.
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20 MeSH Terms
TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities.
Samarakoon R, Overstreet JM, Higgins PJ
(2013) Cell Signal 25: 264-8
MeSH Terms: ErbB Receptors, Fibrosis, Humans, NADPH Oxidases, Oxidation-Reduction, Plasminogen Activator Inhibitor 1, Reactive Oxygen Species, Signal Transduction, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
During development of TGF-β1-initiated fibroproliferative disorders, NADPH oxidases (NOX family members) generate reactive oxygen species (ROS) resulting in downstream transcription of a subset genes encoding matrix structural elements and profibrotic factors. Prominent among the repertoire of disease-implicated genes is the TGF-β1 target gene encoding the potent profibrotic matricellular protein plasminogen activator inhibitor-1 (PAI-1 or SERPINE1). PAI-1 is the major physiologic inhibitor of the plasmin-based pericellular cascade and a causative factor in the development of vascular thrombotic and fibroproliferative disorders. ROS generation in response to TGF-β1 stimulation is rapid and precedes PAI-1 induction; engagement of non-SMAD (e.g., EGFR, Src kinase, MAP kinases, p53) and SMAD2/3 pathways are both required for PAI-1 expression and are ROS-dependent. Recent findings suggest a novel role for p53 in TGF-β1-induced PAI-1 transcription that involves ROS generation and p53/SMAD interactions. Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-β1 signaling.
Copyright © 2012 Elsevier Inc. All rights reserved.
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12 MeSH Terms