(Circulation. 2000;101:1773.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Ciprofibrate Therapy Improves Endothelial Function and Reduces Postprandial Lipemia and Oxidative Stress in Type 2 Diabetes Mellitus
From the Cardiovascular Sciences Research Group, University Hospital of Wales, Cardiff (M.E., R.A.A., G.R.E., S.D., S.K.J., M.J.L., M.P.F., A.R.); Department of Biomedical Sciences, University of Wales Institute, Cardiff (K.M.); and Department of Biochemistry, Liverpool John Moores University, Liverpool, UK (J.G.).
Correspondence to Dr L.M. Evans, Department of Diabetes and Endocrinology, C/O Ward B7, University Hospital of Wales, Heath Park, Cardiff, Wales CF4 4XW. E-mail morgancl{at}cf.ac.uk
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Abstract |
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Background—Exaggerated postprandial lipemia (PPL) is a factor in atherogenesis, involving endothelial dysfunction and enhanced oxidative stress. We examined the effect of ciprofibrate therapy on these parameters in type 2 diabetes mellitus.
Methods and Results—Twenty patients entered a 3-month, double-blind, placebo-controlled study. Each subject was studied fasting and after a fatty meal, at baseline, and after 3 months of treatment. Glucose and lipid profiles were measured over an 8-hour postprandial period. Endothelial function (flow-mediated endothelium-dependent vasodilatation [FMD]) and oxidative stress (electron paramagnetic resonance spectroscopy) were measured after fasting and 4 hours postprandially. At baseline, both groups exhibited similar PPL and deterioration in endothelial function. After ciprofibrate, fasting and postprandial FMD values were significantly higher (from 3.8±1.8% and 1.8±1.3% to 4.8±1.1% and 3.4±1.1%; P<0.05). This was mirrored by a fall in fasting and postprandial triglycerides (3.1±2.1 and 6.6±4.1 mmol/L to 1.5±0.8 and 2.8±1.3 mmol/L, P<0.05). Fasting and postprandial HDL cholesterol was also elevated (0.9±0.1 and 0.8±0.1 mmol/L and 1.2±0.2 and 1.2±0.1 mmol/L, P<0.05). There were no changes in total or LDL cholesterol. Fasting and postprandial triglyceride enrichment of all lipoproteins was attenuated, with cholesterol depletion of VLDL and enrichment of HDL. There were similar postprandial increases in oxidative stress in both groups at baseline, which was significantly attenuated by ciprofibrate (0.3±0.6 versus 1.5±1.1 U, P<0.05).
Conclusions—This study demonstrates that fibrate therapy improves fasting and postprandial endothelial function in type 2 diabetes. Attenuation of PPL and the associated oxidative stress, with increased HDL cholesterol levels, may be important.
Key Words: diabetes mellitus • lipemia • endothelium • stress
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Introduction |
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Cardiovascular disease is the most common complication of type 2 diabetes.1 Many established risk factors for atherosclerosis are characteristic of type 2 diabetes. The so-called metabolic syndrome2 includes a dyslipidemia characterized by hypertriglyceridemia, reduced HDL-cholesterol (HDL-C), and abnormal postprandial lipemia (PPL).3 4 5 Recent evidence suggests that glycemia is not the major determinant of coronary heart disease (CHD) in type 2 diabetes,6 with fasting hypertriglyceridemia being an independent predictor of CHD in type 2 diabetes.7 8 Furthermore, fasting hypertriglyceridemia (elevated triglyceride [TG]-rich VLDL) in nondiabetic subjects with normal total and LDL cholesterol levels is associated with endothelial dysfunction (ED).9
PPL represents the state of absorption during which TG metabolism is under challenge. Because many factors involved in postprandial lipid metabolism are insulin sensitive,5 there is potential for abnormalities of PPL to arise in type 2 diabetes. PPL in type 2 diabetes consists of prolonged and exaggerated excursions in plasma TG with subsequent lipoprotein TG enrichment.10 A significant relationship between PPL and coronary atherosclerosis has been described in subjects with and without type 2 diabetes.11 12 After a fatty meal, nondiabetic subjects demonstrate transient ED, which can be attenuated by the antioxidant vitamins C and E.13 No dysfunction is noted after a low-fat meal. Thus, lipoprotein TG enrichment during PPL results in an atherogenic lipoprotein profile, putatively causing enhanced oxidative stress and ED.
Studies have consistently demonstrated the presence of ED in type 2 diabetes.14 These, however, were conducted in patients in the fasting state and may underestimate the true extent of ED in type 2 diabetes.
Fibrates are a widely used class of lipid-regulating agents, exerting a variety of effects on lipid and lipoprotein metabolism,15 particularly attenuation of PPL16 and reduction in TG-rich VLDL. We therefore studied the effect of ciprofibrate therapy on endothelial function, oxidative stress, and PPL in type 2 diabetes in a double-blind, placebo-controlled study.
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Methods |
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Subjects
Twenty type 2 diabetic patients (mean age, 47.5 years; age range, 35 to 53 years; 11 men, 9 women; diagnosis based on WHO criteria) with a mean HbA1C of 8.5% were recruited. All subjects were normotensive nonsmokers with fasting total cholesterol <6.5 mmol/L. Each had a normal resting ECG and no personal or family history of premature vascular disease. A family history of premature vascular disease was defined as the absence of symptomatic macrovascular disease in a first-degree relative before the age of 65 years. All subjects were not taking aspirin, lipid-lowering agents, or supplemental vitamins. Female subjects were premenopausal and were studied at approximately the same time in their menstrual cycles (follicular phase). Written consent was obtained from all subjects, with local ethics committee approval.
Study Protocol
Studies were begun after a 12-hour overnight fast. After 30
minutes of supine rest, venous blood was drawn for measurement of total
cholesterol, LDL-C, HDL-C, plasma TG, insulin, glucose, and
glycosylated HbA1C; 5 mL venous blood was also drawn to measure venous
free radicals. Each subject was given a fatty meal17
containing 80 g saturated fat, and lipid profiles and plasma
glucose were repeated every 2 hours over the following 8 hours.
Endothelial function and oxidative stress were assessed
while the subjects were fasting and during peak lipemia. Each patient
was randomized to 3-month treatment with either ciprofibrate 100 mg
once daily or matched placebo, after which the above inv estigations
were repeated.
Endothelial Function Assessment
Changes in brachial artery diameter in response to reactive
hyperemia (FMD) and sublingual NTG (400 µg)
(endothelium-independent dilatation) were measured with
an ultrasonic vessel wall-tracking system (resolution, ±3 µm)
as previously described and validated.18 Vasodilatation
data are presented as percentage change from resting vessel
diameter.
Biochemical Measurements
Total cholesterol and TG concentrations were
measured enzymatically.19 20 HDL-C concentrations were
measured after precipitation of apolipoprotein B with
phosphotungstate/magnesium.21 LDL-C was calculated after
lipoprotein separation.22 Plasma glucose was measured by a
hexokinase-based technique, HbA1C via enzyme
immunoassay,23 and plasma insulin by a commercial
radioimmunoassay (INS-RIA-100, Medgenix Diagnostics).
Lipoprotein Separation
Blood was collected into EDTA tubes, and the plasma was prepared
by centrifugation at 20 000g for 20
minutes. Chylomicrons were removed by centrifugation at
20 000g for 20 minutes. Then, 2.4 mL chylomicron-free
plasma was placed in a tube containing 0.6 mL iodixanol (Liposep) and
centrifuged.22 Gradient fractions were
collected by tube puncture into a multiwell plate and analyzed
for cholesterol and TG (with commercial
diagnostic kits). By plotting cholesterol and
TG profiles of gradients, we identified the fractions containing HDL,
LDL, and VLDL and confirmed them by agarose gel electrophoresis of the
appropriate fractions. Total cholesterol and TG in each
lipoprotein class were calculated by summation of the amounts of these
lipids in those fractions corresponding to each lipoprotein class.
Total concentrations of HDL and LDL may also be calculated with this
methodology.22
Free Radical Measurement
Ex vivo spin trapping was used to measure free radicals in
venous blood.24 25 Reactive oxygen species induce lipid
peroxidation, producing secondary lipid radicals, which are detectable
by EPR spectroscopy when spin trapped.26 Then, 2.5 mL
venous blood was taken directly in sealed glass tubes containing 1 mL
of the spin trap, 
-phenyl-N-tert-butyl nitrone (PBN)
(0.125 mol/L). After centrifugation, the PBN adduct was
extracted from plasma supernatant with toluene, dried under nitrogen
gas, and reconstituted in degassed chloroform. EPR spectra were
recorded on a Varian E104 spectrometer operating at 9.1 GHz at
10-MW power, 1-G modulation, 0.25-second time constant, and 100-G scan
range. EPR spectral parameters were obtained from data
acquisition and processing with EPR computational software. EPR
spectral peak heights were taken as a good correlation of spin-adduct
concentration after confirmation of peak-to-peak line width conformity
and double integration on selected samples and expressed in arbitrary
units. Analysis of the EPR spectra from spin-trapped radicals
suggests that alkoxyl radicals (coupling constants, aN=13.9 G,
aßH=2.2 G) and carbonyl radicals (aN=14.1 G, aßH=4.0 G) are
trapped, which is in agreement with previous
studies.27
Statistical Analysis
Conventional methods were used for calculating mean, SD, and
checks for normal distribution. Group differences in continuous
variables were determined by a 2-tailed t test.
Statistical significance for differences in continuous variables
between groups was tested by 1-way ANOVA. As a measure of plasma
glucose and the total amounts of lipid and lipoprotein present in
plasma during PPL, AUCs were calculated for plasma concentrations
without subtraction of baseline values. This measure of AUC was used
because the principle aim of this study was to investigate the effect
of PPL on fasting measures of endothelial function and
oxidative stress. Multiple regression analysis was used to
study the independent relationship between variables with
logarithmic transformation of skewed data. Statistical significance was
inferred at P<0.05.
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Results |
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Patient Characteristics
There were no differences in blood pressure or body mass index between groups at baseline and after treatment (Table 1
).
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Biochemistry
There were no differences in total, LDL cholesterol,
insulin, glucose, and HbA1C between groups at baseline and after
treatment (Table 2). There was a
significant reduction in fasting plasma TG and increase in HDL-C after
ciprofibrate. Table 3 illustrates the
fasting VLDL, LDL, and HDL compositional changes after placebo and
ciprofibrate.
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Postprandial Lipemia
Area under the curve (AUC) for postprandial plasma TG (mmol
· L-1 · 8 h-1)
was similar in both groups at baseline (199.8±98 for ciprofibrate,
188.6±110 for placebo). There was a significant reduction in
postprandial hypertriglyceridemia after
ciprofibrate (Figure 1), resulting in
reduced plasma TG AUC (199.8±98 at baseline, 78.9±21.6 at 3 months;
P<0.05). No changes were noted after placebo (Figure 2).
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AUC for TG content of HDL, LDL, and VLDL was initially similar in both
groups (Table 3
). After ciprofibrate, postprandial lipoprotein
TG enrichment was significantly reduced (Table 4). There was no significant increase in
glucose between fasting and 4-hour levels. Postprandial glycemia (AUC
glucose) was not changed by treatment.
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Vascular Data
At baseline, fasting and postprandial flow-mediated
endothelium-dependent vasodilatation (FMD) was similar
in both groups, with a significant reduction in postprandial FMD
(Figure 3). Fasting FMD significantly
improved in the ciprofibrate group (3.8±1.8% versus 4.8±1.1%,
P<0.05). Similarly, postprandial FMD improved significantly
(1.8±1.3% versus 3.4±1.1%, P<0.05). There were no
changes after placebo (Figure 3). Nitroglycerin
(NTG)-mediated vasodilatation was similar in both groups, with no
changes after treatment (Figure 4).
Fasting and postprandial resting arterial diameter and
resting and hyperemic blood flow were similar in both groups
before and after treatment.
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Free Radical Data
Both groups initially exhibited similar measures of fasting and
postprandial oxidative stress (fasting: 2.33±1.1 for ciprofibrate,
2.4±1.8 for placebo; postprandial: 3.85±2.5 for ciprofibrate,
3.7±2.9 for placebo; Figure 5). After
treatment, fasting oxidative stress was similar in both groups with no
change from baseline (2.27±1.3 for ciprofibrate, 2.36±1.5 for
placebo). Ciprofibrate attenuated the postprandial excursion in
oxidative stress (2.57±1.9 versus 3.89±2.5, P<0.05).
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Correlation Between PPL, Endothelial Function, and
Oxidative Stress
Fasting FMD correlated inversely with LDL cholesterol
(LDL-C) (r=-0.55, P=0.03 for ciprofibrate;
r=-0.52, P=0.02 for placebo) and TG content of
VLDL (r=-0.51, P=0.03 for ciprofibrate;
r=-0.50, P=0.04 for placebo). HDL-C correlated
positively with FMD (r=0.52, P=0.03 for
ciprofibrate; r=0.55, P=0.02 for placebo). The
postprandial reduction in FMD correlated with postprandial TG
enrichment of VLDL (r=0.52, P=0.04 for
ciprofibrate; r=0.54, P=0.03 for placebo) and LDL
(r=0.55, P=0.03 for ciprofibrate;
r=0.52, P=0.04 for placebo) and inversely with
4-hour HDL-C (r=-0.57, P=0.02 for ciprofibrate;
r=-0.54, P=0.03 for placebo). Fasting oxidative
stress demonstrated no significant correlations. The postprandial
increase in oxidative stress correlated with postprandial TG enrichment
of VLDL (AUC for VLDL TG content) (r=0.51, P=0.04
for ciprofibrate; r=0.53, P=0.03 for placebo).
After treatment, there were no significant correlations (at the 95%
confidence level) between the fasting and postprandial improvement in
endothelial function and any changes in the measured
metabolic parameters as a result of
ciprofibrate therapy.
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Discussion |
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This study demonstrates an association between exaggerated PPL with the production of atherogenic lipoproteins, enhanced oxidative stress, and augmented ED in type 2 diabetes, which is attenuated by ciprofibrate.
Fasting endothelial function correlated inversely with LDL-C levels and TG content of VLDL and positively with HDL-C levels. The postprandial deterioration in endothelial function correlated inversely with HDL-C and positively with the postprandial TG enrichment of VLDL and LDL. Postprandial TG enrichment of VLDL was the only parameter to correlate with postprandial oxidative stress. There was also a trend toward reduced postprandial NTG responsiveness, which has been previously described in other studies examining the effects on of transient hypertriglyceridemia on endothelial function.28 This effect may due partly to increased free fatty acid levels, which may downregulate smooth muscle responsiveness to nitric oxide (NO).29
Associations between endothelial function, LDL-C, and HDL-C in type 2 diabetes have been previously described.30 This study demonstrates a direct association between TG-rich lipoproteins and ED, both fasting and postprandial in type 2 diabetes. Furthermore, we report an association between TG-rich VLDL and enhanced oxidative stress in type 2 diabetes.
Lipoprotein analysis from the Monitored Atherosclerosis Regression Study (MARS)31 demonstrated the importance of TG-rich VLDL and IDL as predictors of atherosclerotic disease progression. TG-rich VLDL particles preferentially undergo endocytosis by receptors on macrophages to form foam cells.32 Furthermore, lipolytic products of TG-rich VLDL are toxic to endothelial cells and macrophages.33 34 TG-rich apolipoprotein B–containing particles have also been isolated in excess from atherosclerotic plaques.34 Increased free fatty acid fluxes, particularly during PPL, may potentate the effects of TG-rich VLDL on endothelial function, because VLDL causes enhanced endothelial toxicity when FFA/albumin ratios are elevated.35
TG enrichment of VLDL also affects LDL metabolism,36 with increased synthesis of atherogenic small, dense LDL particles, which are toxic to endothelial cells and exhibit enhanced pro-oxidant potential.37
During PPL, there was TG enrichment of LDL and HDL particles. Hydrolysis of TG in these TG-rich LDL particles contributes further to the production of smaller, denser particles. TG-rich, cholesterol-depleted HDL particles, produced partly as a result of enhanced neutral lipid exchange with TG-rich VLDL, demonstrate decreased endothelium-protective properties, including reduced antioxidant properties.38
Not only are these particles produced in excess during PPL in type 2 diabetes, there is also reduced particle catabolism as a result of impaired lipoprotein lipase function5 and defective particle clearance as a result of increased particle competition for receptor-mediated endocytosis.29 Functional lipoprotein lipase is required to produce such an atherogenic lipoprotein profile and thus mediate the effects of hypertriglyceridemia on endothelial function, because in hypertriglyceridemic patients with lipoprotein lipase deficiency, endothelial function is preserved.39
Type 2 diabetes is associated with enhanced oxidative stress,40 representing a state of disequilibrium between free radical production and antioxidant defenses. This study supports an association between transient hypertriglyceridemia and the production of TG-rich VLDL particles during PPL in type 2 diabetes with increased oxidative stress. The precise mechanisms accounting for this observation remain speculative and may involve a variety of complex changes in lipoprotein metabolism.38
Enhanced oxidative stress has a variety of important effects in atherogenesis, including lipoprotein oxidation, particularly LDL oxidation41 ; this may be of particular relevance in type 2 diabetes. Oxidized LDL has both pro-oxidant properties and enhanced endothelial toxicity.42 Enhanced oxidative stress may also directly induce ED by decreasing synthesis and release of NO by endothelial cells and by inactivating NO in the subendothelial space.38 Furthermore, the alkoxyl radicals detected by electron paramagnetic resonance (EPR) spectroscopy have been shown to directly interact with NO.43 Thus, our observation of deteriorating endothelial function associated with PPL in type 2 diabetes may result from a combination of dyslipidemia and oxidative stress.
After ciprofibrate, fasting and postprandial endothelial function significantly improved, coupled with a reduction in postprandial oxidative stress. Fasting plasma TG and postprandial AUC for TG were also reduced, whereas HDL-C levels were increased. There were also modest but nonsignificant reductions in total and LDL cholesterol, plasma insulin, and HbA1C. Furthermore, there was TG depletion of all lipoproteins, with cholesterol enrichment of HDL and cholesterol depletion of VLDL.
The nonsignificant reduction in fasting insulin and HbA1C may reflect improved insulin sensitivity, and because this positively relates to endothelial NO synthesis,44 it could potentially account for some of the observed change in endothelial function. However, improved fasting endothelial function correlates most strongly with reduced fasting plasma TG and TG depletion of VLDL and HDL (r=0.54, 0.46, and 0.48, respectively). Moreover, the improvement in postprandial endothelial function correlates most strongly with attenuation of postprandial hypertriglyceridemia and lipoprotein TG enrichment. Additionally, the changes in postprandial oxidative stress correlate most strongly with attenuation of VLDL TG enrichment. These correlations were not significant at the 95% confidence level, which may be due to the relatively small sample size and small absolute differences rather than to a true lack of biological significance.
Fibrates cause decreased production and enhanced catabolism of TG-rich VLDL.15 Subsequently, there is reduced neutral lipid exchange, resulting in TG depletion of LDL and HDL with cholesterol enrichment of increased concentrations of HDL. This results in production of larger, less dense particles with reduced atherogenic potential, which may be of even greater significance during PPL.
The mechanisms by which ciprofibrate improves endothelial function and oxidative stress during PPL remain speculative Attenuating the magnitude and duration of the exposure of the endothelium to atherogenic lipoproteins may be of benefit, with reduced TG-rich VLDL particles and increased HDL-C levels being of particular importance.
In summary, we confirm that PPL in type 2 diabetes results in ED and enhanced oxidative stress. Ciprofibrate therapy, by attenuating PPL and modifying an atherogenic lipoprotein profile, leads to significant improvement in fasting and postprandial endothelial function and attenuated postprandial oxidative stress.
Study Limitations
This study evaluates the effect of ciprofibrate therapy on
potential atherogenic mechanisms in type 2 diabetes. A
hypertriglyceridemic nondiabetic control
group may have provided some interesting data. However,
hypertriglyceridemia is
heterogeneous with different clinical phenotypes,
is associated with different degrees of cardiovascular
risk, is a cardinal feature of the insulin resistance syndrome, and may
be considered a marker of impaired glucose tolerance. Indeed, a
significant progression from
hypertriglyceridemia to overt type 2
diabetes mellitus is well recognized. Additionally, the basic
metabolic disorders accounting for
hypertriglyceridemia—namely, reduced
lipoprotein lipase activity, increased circulating fasting and
postprandial free fatty acids, and enhanced neutral lipid exchange—are
also typical of the dyslipidemia of type 2 diabetes. Thus,
the inclusion of such a control group would do little to address the
original questions posed.
Received August 13, 1999; revision received November 15, 1999; accepted November 29, 1999.
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  U. Sen, W. E. Rodriguez, N. Tyagi, M. Kumar, S. Kundu, and S. C. Tyagi Ciglitazone, a PPAR{gamma} agonist, ameliorates diabetic nephropathy in part through homocysteine clearance Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1205 - E1212. [Abstract] [Full Text] [PDF]
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 K. M. Maki-Petaja, A. D. Booth, F. C. Hall, S. M.L. Wallace, J. Brown, C. M. McEniery, and I. B. Wilkinson Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis J. Am. Coll. Cardiol., August 28, 2007; 50(9): 852 - 858. [Abstract] [Full Text] [PDF]
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 R. S. Rosenson, D. A. Wolff, A. L. Huskin, I. B. Helenowski, and A. W. Rademaker Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome Diabetes Care, August 1, 2007; 30(8): 1945 - 1951. [Abstract] [Full Text] [PDF]
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 S. J Hamilton, G. T Chew, and G. F Watts Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 89 - 102. [Abstract] [PDF]
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 M. Negrean, A. Stirban, B. Stratmann, T. Gawlowski, T. Horstmann, C. Gotting, K. Kleesiek, M. Mueller-Roesel, T. Koschinsky, J. Uribarri, et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1236 - 1243. [Abstract] [Full Text] [PDF]
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 E. Gkaliagkousi, A. Shah, and A. Ferro Review: Pharmacological and non-pharmacological treatment of endothelial dysfunction: relevance to diabetes The British Journal of Diabetes & Vascular Disease, January 1, 2007; 7(1): 5 - 10. [Abstract] [PDF]
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 W. E. Rodriguez, N. Tyagi, I. G. Joshua, J. C. Passmore, J. T. Fleming, J. C. Falcone, and S. C. Tyagi Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus Am J Physiol Renal Physiol, September 1, 2006; 291(3): F694 - F701. [Abstract] [Full Text] [PDF]
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 W. E. Rodriguez, I. G. Joshua, J. C. Falcone, and S. C. Tyagi Pioglitazone prevents cardiac remodeling in high-fat, high-calorie-induced Type 2 diabetes mellitus Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H81 - H87. [Abstract] [Full Text] [PDF]
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 A. Zambon, P. Gervois, P. Pauletto, J.-C. Fruchart, and B. Staels Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR-{alpha} Activators: Clinical and Experimental Evidence Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 977 - 986. [Abstract] [Full Text] [PDF]
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 S. H. Han, M. J. Quon, and K. K. Koh Beneficial Vascular and Metabolic Effects of Peroxisome Proliferator-Activated Receptor-{alpha} Activators Hypertension, November 1, 2005; 46(5): 1086 - 1092. [Abstract] [Full Text] [PDF]
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K. K. Koh, S. H. Han, M. J. Quon, J. Yeal Ahn, and E. K. Shin Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia Diabetes Care, June 1, 2005; 28(6): 1419 - 1424. [Abstract] [Full Text] [PDF]
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R. A Anderson, G. R Ellis, L. M. Evans, K. Morris, Y. Y Chirkov, J. D Horowitz, S. K Jackson, A. Rees, M. J Lewis, and M. P Frenneaux Platelet nitrate responsiveness in fasting and postprandial type 2 diabetes Diabetes and Vascular Disease Research, May 1, 2005; 2(2): 88 - 93. [Abstract] [PDF]
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B. Cariou, J.-C. Fruchart, and B. Staels Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists The British Journal of Diabetes & Vascular Disease, May 1, 2005; 5(3): 126 - 132. [Abstract] [PDF]
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 S. P. Zhao, L. Liu, Y. C. Cheng, M. H. Shishehbor, M. H. Liu, D. Q. Peng, and Y. L. Li Xuezhikang, an Extract of Cholestin, Protects Endothelial Function Through Antiinflammatory and Lipid-Lowering Mechanisms in Patients With Coronary Heart Disease Circulation, August 24, 2004; 110(8): 915 - 920. [Abstract] [Full Text] [PDF]
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 N. Marx, H. Duez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circ. Res., May 14, 2004; 94(9): 1168 - 1178. [Abstract] [Full Text] [PDF]
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G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]
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 R.A. Anderson, G.R. Ellis, Y.Y. Chirkov, A.S. Holmes, N. Payne, D.J. Blackman, S.K. Jackson, M.J. Lewis, J.D. Horowitz, and M.P. Frenneaux Determinants of platelet responsiveness to nitric oxide in patients with chronic heart failure Eur J Heart Fail, January 1, 2004; 6(1): 47 - 54. [Abstract] [Full Text] [PDF]
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 D. K. Plante and J. L. Nadler Diabetes and Vascular Disease Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 295 - 310. [Abstract] [PDF]
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W. G. Haynes Triglyceride-Rich Lipoproteins and Vascular Function Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 153 - 155. [Full Text] [PDF]
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W. H. Capell, C. A. DeSouza, P. Poirier, M. L. Bell, B. L. Stauffer, K. M. Weil, T. L. Hernandez, and R. H. Eckel Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 307 - 313. [Abstract] [Full Text] [PDF]
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 H. S. Sood, M. J. Hunt, and S. C. Tyagi Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L333 - L341. [Abstract] [Full Text] [PDF]
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 M. Guerin, P. Egger, W. Le Goff, C. Soudant, R. Dupuis, and M. J. Chapman Atorvastatin Reduces Postprandial Accumulation and Cholesteryl Ester Transfer Protein-Mediated Remodeling of Triglyceride-Rich Lipoprotein Subspecies in Type IIB Hyperlipidemia J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4991 - 5000. [Abstract] [Full Text] [PDF]
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 M. J. Hunt and S. C. Tyagi Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1073 - C1079. [Abstract] [Full Text] [PDF]
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 F. W. Booth, M. V. Chakravarthy, S. E. Gordon, and E. E. Spangenburg Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy J Appl Physiol, July 1, 2002; 93(1): 3 - 30. [Abstract] [Full Text] [PDF]
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R. W. van Etten, E. J.P. de Koning, M. L. Honing, E. S. Stroes, C. A. Gaillard, and T. J. Rabelink Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 799 - 804. [Abstract] [Full Text] [PDF]
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M. Kelm Flow-mediated dilatation in human circulation: diagnostic and therapeutic aspects Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H1 - H5. [Full Text] [PDF]
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 J. Malik, V. Melenovsky, D. Wichterle, T. Haas, J. Simek, R. Ceska, and J. Hradec Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial -- FAT) Cardiovasc Res, November 1, 2001; 52(2): 290 - 298. [Abstract] [Full Text] [PDF]
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 A. D. Sniderman, T. Scantlebury, and K. Cianflone Hypertriglyceridemic HyperapoB: The Unappreciated Atherogenic Dyslipoproteinemia in Type 2 Diabetes Mellitus Ann Intern Med, September 18, 2001; 135(6): 447 - 459. [Abstract] [Full Text] [PDF]
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 K.-i. Inoue, Y. Kawahito, T. Yoshikawa, H. Sano, J. L. Houghton, and M. T. Torosoff Lipid-Lowering Agents and Artery Endothelial Function Chest, June 1, 2001; 119(6): 1979 - 1980. [Full Text] [PDF]
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 J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF]
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A. K. Nightingale, P. P. James, J. Morris-Thurgood, F. Harrold, R. Tong, S. K. Jackson, J. R. Cockcroft, and M. P. Frenneaux Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1334 - H1339. [Abstract] [Full Text] [PDF]
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G. R. Ellis, R. A. Anderson, D. Lang, D. J. Blackman, R. H. K. Morris, J. Morris-Thurgood, I. F. W. McDowell, S. K. Jackson, M. J. Lewis, and M. P. Frenneaux Neutrophil superoxide anion-generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1474 - 1482. [Abstract] [Full Text] [PDF]
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V. S. Mujumdar, C. M. Tummalapalli, G. M. Aru, and S. C. Tyagi Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR Am J Physiol Cell Physiol, May 1, 2002; 282(5): C1009 - C1015. [Abstract] [Full Text] [PDF]
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