Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)

Ruotolo, Giacomo; Ericsson, Carl‐Göran; Tettamanti, Cristina; Karpe, Fredrik; Grip, Lars; Svane, Bertil; Nilsson, Jan; Fairé, Ulf dé; Hamsten, Anders

doi:10.1016/s0735-1097(98)00442-2

Cited by 158 publications

(93 citation statements)

References 33 publications

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“…[3][4][5] Such effects may be attributable at least in part to their effects on lipoprotein abnormalities, which are mainly exerted by PPAR␣ expressed in the liver. Several studies 9,10,17,18 have demonstrated that PPAR␣ is also expressed in vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Diabetes Atherosclerosis Intervention Study (DAIS) 5 as well as Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) 3,4 suggest that treatment with fenofibrate or bezafibrate reduces the progression of coronary artery disease. It is thought that such effects are related, at least partly, to the correction of lipoprotein abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…2 There has been accumulating evidence showing that fibrates have favorable effects of slowing the progression of atherosclerosis and reducing the number of events of coronary heart diseases in high-risk patients. [3][4][5] PPAR␣ is known to be expressed in the liver, which is mainly involved in lipid and lipoprotein metabolism exerted by fibrates. 1 In addition, recent studies have shown that PPAR␣ is also expressed in the cardiovascular system, including heart and vascular wall component cells such as vascular endothelial, vascular smooth muscle, and monocyte cells, and performs a direct antiatherogenic and antiinflammatory action.…”

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confidence: 99%

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Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Goya

Sumitani

et al. 2004

ATVB

167

111

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Objective-There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor ␣ (PPAR␣) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR␣ activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. Methods and Results-Bovine aortic endothelial cells were treated with the PPAR␣ activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR␣ action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. Conclusions-PPAR␣ activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR␣-mediated cardiovascular protection. Key Words: atherosclerosis Ⅲ endothelium Ⅲ nitric oxide Ⅲ vascular biology Ⅲ vasodilatation H ypolipidemic fibrates are pharmacological compounds that activate peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the nuclear hormone receptor superfamily. 1 These fibrates have been widely used as effective drugs lowering serum triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol. 2 There has been accumulating evidence showing that fibrates have favorable effects of slowing the progression of atherosclerosis and reducing the number of events of coronary heart diseases in high-risk patients. 3-5 PPAR␣ is known to be expressed in the liver, which is mainly involved in lipid and lipoprotein metabolism exerted by fibrates. 1 In addition, recent studies have shown that PPAR␣ is also expressed in the cardiovascular system, including heart and vascular wall component cells such as vascular endothelial, vascular smooth muscle, and monocyte cells, and performs a direct antiatherogenic and antiinflammatory action. 6 Staels et al have shown that PPAR␣ ligands inhibit interleukin (IL)-1-induced expression of IL-6, prostaglandin, and cyclooxygenase 2 in aortic smooth muscle cells. 7 These authors further showed that patients receiving fenofibrate, a potent fibrate, had lower plasma C-reactive protein, fibrinogen, and IL-6 concentrations. 7 Furthermore, it has been demonstrated that PPAR␣ activators inhibit cytokine-induced vascular cell adhesion molecule-1 (VCAM-1), 8,9 and thrombin-induced endothelin-1 expression 10 in vascular en...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Goya

Sumitani

et al. 2004

ATVB

167

111

View full text Add to dashboard Cite

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“…These agents regulate lipid metabolism by reducing triglycerides and increasing HDL cholesterol as well as by modulating LDL cholesterol, shifting the balance towards large buoyant, less-atherogenic particles [1,2]. More recently it has been postulated that fibrates exert antiatherogenic actions independently of their effects on lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

et al. 2006

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“…Similarly, the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) documented a shift in the low density lipoprotein subclass distribution towards larger particle species [77] in the treatment group. Finally, when gemfibrozil was compared to atorvastatin, it was more effective in increasing LDL size compared to the statin group in patients with type 2 diabetes [61].…”

Section: Lipid Lowering Agents Targeting Ldl Particle Distributionmentioning

confidence: 99%

Small dense low-density lipoprotein particles: priority as a treatment target in Type 2 diabetes?

Gerber¹,

Spinas²,

Berneis³

2012

Diabetes Management

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During the past two decades, the importance of the quality of low-density lipoprotein (LDL) particles -in addition to its quantity -has become of increasing interest. The risk of cardiovascular events was recognized to be closely linked to a predominance of small, dense LDL particles. In addition, in patients with Type 2 diabetes mellitus, the disease itself and its severity (in particular the degree of insulin resistance) is associated with this subclass of LDL particles. Lipid lowering as well as antihyperglycemic drugs have been evaluated in many studies concerning their effect on LDL particle size. It has increasingly been recognized that a reduction of LDL quantity is not necessarily associated with a beneficial effect on LDL quality. Advances in the understanding of alterations in LDL quality may therefore influence the choice of the therapeutic regimen in patients with diabetes in the future. SummaryDuring the last two decades, the importance of the quality of low-density lipoprotein (LDL) particles -in addition to its quantity -has become of increasing interest. The risk of cardiovascular events was recognized to be closely linked to a predominance of small, dense LDL particles. In addition, in patients with type 2 diabetes mellitus, the disease itself and its severity (in particular the degree of insulin resistance) is associated with this subclass of LDL particles. Lipid lowering as well as antihyperglycemic drugs have been evaluated in many studies concerning their effect on LDL particle size. It has increasingly been recognized that a reduction of LDL quantity is not necessarily associated with a beneficial effect on LDL quality. Advances in the understanding of alterations in LDL quality may therefore influence the choice of the therapeutic regimen in patients with diabetes in the future.

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Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)

Abstract: Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.

Cited by 158 publications

References 33 publications

Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

Small dense low-density lipoprotein particles: priority as a treatment target in Type 2 diabetes?

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