Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation
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TLDR
This study demonstrates that gemfibrozil exerts anti-atherogenic actions, independently of changes in cholesterol and glucose metabolism, and emphasise the possible usefulness of fibrates such as gemfiber in a setting of atherosclerosis even in the absence of dyslipidaemia.Abstract:
It is postulated that peroxisome proliferator-activated receptor α agonists confer cardiovascular benefits in diabetes, independently of their effects on lipid metabolism. We investigated putative mechanisms responsible for these anti-atherogenic effects in an in vivo model of diabetes-associated atherosclerosis. Control and streptozotocin-induced diabetic apolipoprotein-deficient mice received gemfibrozil (100 mg kg−1 day−1) or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent en face quantification. Superoxide production was measured using lucigenin-enhanced chemiluminescence. Markers of pathways including inflammation and oxidative stress were measured using real-time RT-PCR. No significant effect of gemfibrozil was observed on glycated haemoglobin, cholesterol or insulin in diabetic mice. Diabetes was associated with a three-fold increase in plaque area and a significant increase in NADPH-dependent superoxide compared with control mice. Gemfibrozil significantly attenuated plaque area and superoxide production in diabetic mice. In addition, gemfibrozil reduced the expression of the genes encoding the NADPH oxidase subunits p47phox, gp91phox and Rac-1. In addition, gemfibrozil reduced the expression of the genes encoding nuclear factor kappa B (NF-κB) subunit, p65, the NF-κB-dependent chemokine monocyte chemoattractant protein-1, and tissue factor. This study demonstrates that gemfibrozil exerts anti-atherogenic actions, independently of changes in cholesterol and glucose metabolism. Such findings emphasise the possible usefulness of fibrates such as gemfibrozil in a setting of atherosclerosis even in the absence of dyslipidaemia.read more
Citations
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Mouse Models for Atherosclerosis and Pharmaceutical Modifiers
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References
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Journal ArticleDOI
Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol
Hanna Bloomfield Rubins,Sander J. Robins,Dorothea Collins,Carol L. Fye,James W. Anderson,Marshall B. Elam,Fred H. Faas,Esteban Linares,Ernst J. Schaefer,Gordon Schectman,Timothy J Wilt,Janet Wittes +11 more
TL;DR: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level, suggesting that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.
Journal ArticleDOI
NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
TL;DR: Vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix and have been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
Journal ArticleDOI
Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.
TL;DR: A method is devised which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections and may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.
Journal ArticleDOI
Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)
R. C. Turner,H Millns,H. A. W. Neil,Irene M Stratton,Susan E. Manley,David R. Matthews,Rury R. Holman +6 more
TL;DR: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus, which are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density cholesterol, raised blood pressure, hyperglycaemia, and smoking.
Journal ArticleDOI
Oxidative Stress and Diabetic Vascular Complications
TL;DR: The suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status is suggested.
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