Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia

Haak, Eva; Abletshauser, C.; Weber, Stephan; Goedicke, Christine; Martin, Nicole; Hermanns, N; Lackner, Karl J.; Kusterer, Klaus; Usadel, K. H.; Haak, Thomas

doi:10.1016/s0021-9150(00)00567-0

Cited by 44 publications

(27 citation statements)

References 34 publications

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“…Newaz et al (32) reported that PPAR-␣ activators amplify inducible NOS (iNOS) expression and increased renal NO production as measured by urinary excretion of nitrite/nitrate (32). It has been reported that fenofibrate is likely to improve endothelial function by restoring the impaired formation or efficacy of the endothelium-derived relaxing factor such as NO (16,34). Our studies suggest that fenofibrate improves acetylcholine-induced dilation at lower doses partly via modulating vascular NOS and COX pathways.…”

Section: Discussionsupporting

confidence: 54%

“…Fenofibrate has been reported to retard angiographic progression of coronary atherosclerosis in diabetic patients (37) and to improve the microcirculation of patients with hyperlipidemia (25). Although direct activation of PPAR-␣ in arterial wall (12), correction of lipid abnormalities (4,5,30), and increasing the formation, availability, and action of NO (16,34) have all been postulated, the mechanisms responsible for the beneficial effects of fenofibrate on vascular function has not been fully elucidated. More recent studies have demonstrated that treatment with the PPAR-␣ activator fenofibrate induced renal CYP2C23-dependent arachidonic acid-epoxygenase activity and protected double-transgenic rats (dTGRs) from hypertension and inflammatory end-organ damage (29).…”

Section: Discussionmentioning

confidence: 99%

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PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Zhao¹,

Quigley²,

Yuan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg.kg(-1).day(-1) for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 microM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% +/- 11%) compared with lean controls (67% +/- 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 microM of acetylcholine in obese Zucker rats (69% +/- 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-alpha agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Zhao¹,

Quigley²,

Yuan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Short-term oral administration of a statin ameliorated endothelial dysfunction in early atherosclerosis similar to what has been described in previous reports [5,[30][31][32][33] . This effect was thought to lead to an improvement of intestinal PO 2 ratio after nonpulsatile and lowpressure blood fl ow in group S. But this study was the fi rst to demonstrate the ability of statins to inhibit intestinal enzymatic iNOS activity in early atherosclerosis.…”

Section: Pitavastatin Prevents Bacterial Translocationsupporting

confidence: 87%

Pitavastatin Prevents Bacterial Translocation after Nonpulsatile/Low-Pressure Blood Flow in Early Atherosclerotic Rat: Inhibition of Small Intestine Inducible Nitric Oxide Synthase

Tsunooka

Nakagawa²,

Doi³

et al. 2005

Eur Surg Res

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Background: Cardiopulmonary bypass decreases intestinal mucosal blood flow because of nonpulsatile and low-pressure blood flow resulting in bacterial translocation (BT) and atherosclerosis also has peripheral blood flow deficiency. The risk of nonpulsatile and low-pressure blood flow for atherosclerotic animals and the effect of statin administration, which has pleiotropic effects, were studied. Methods: Wistar rats were divided into four groups: group N (normal diet), group C (high-cholesterol diet), group S (group C plus pitavastatin therapy), and group I [group C plus inducible nitric oxide (iNOS) inhibitor therapy]. First of all, vascular responses were measured. Then the rats underwent nonpulsatile/low-pressure blood flow in the intestine, and the serum peptidoglycan concentration as a parameter of BT, the small intestinal PO₂ ratio (intestinal PO₂/PaO₂) as a parameter of mucosal blood flow, and NO concentrations were measured before surgery (T0), at the end of 90 min of stenosis (T1), and 90 min after the release of stenosis (T2). Immunostaining for nitrotyrosine was also performed at T2. Results: Group C had vascular endothelial dysfunction without histological changes, which indicated early atherosclerosis. The serum peptidoglycan concentration increased significantly at T2 only in group C. The intestinal PO₂ ratio was decreased at T1 in all the groups, and retuned to baseline at T2 in group N and group S, but not in group C or group I. Jejunal NO only in group C was significantly higher at all time points and ileal NO production at T1 and T2. There tended to be a positive stain for nitrotyrosine along the mucosal epithelium in group C. Conclusion: In the setting of early atherosclerosis, intestinal blood flow does not only improve after nonpulsatile/low-pressure blood flow but causes BT because of a large amount of NO from high enzymatic intestinal iNOS activity, and pitavastatin treatment can prevent BT by improving both issues.

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“…Treatment with fenofibrate has been shown to improve microcirculatory function in a previous clinical study in dyslipidaemic patients, accompanied by decreased circulating levels of fibrinogen. 34 Fenofibrate has also been shown to improve endothelial function in patients with type 2 diabetes 35 (although another study demonstrated no effect on type 2 diabetes patients with near-normal lipid levels 36 ), and an antiinflammatory effect has been demonstrated in patients with hypercholesterolaemia. 37 Finally, an anti-inflammatory and anti-apoptotic effect of fenofibrate, associated with activation of the cellular energy sensor, AMP-activated protein kinase, has been demonstrated in vitro on cultured human glomerular 38 or retinal 39 microvascular endothelial cells.…”

Section: Mechanisms and Implicationsmentioning

confidence: 99%

Non-invited Review: Prevention of microvascular diabetic complications by fenofibrate: lessons from FIELD and ACCORD

Hermans

2011

Diabetes and Vascular Disease Research

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Microvascular complications are common in type 2 diabetes in primary care. Intensified management of glycaemia or blood pressure had little effect on microvascular complication rates in recent large trials (ADVANCE, VADT, ACCORD). In 2005, the FIELD study demonstrated a significant reduction in the need for laser treatment for retinopathy, and of progression of renal dysfunction, with fenofibrate versus placebo. The FIELD ophthalmology sub-study showed that fenofibrate reduced the risk of new retinopathy and progression of retinopathy. Also, fenofibrate versus placebo significantly reduced the risk of non-traumatic, diabetes-related amputations in a post-hoc analysis from FIELD. Recently, the results of the ACCORD Lipid study were consistent with these findings, as fenofibrate significantly reduced progression of retinopathy and albuminuria, apparently independent of effects on lipids. These findings suggest a role for fenofibrate in the prevention of major diabetic microvascular complications.

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Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia

Cited by 44 publications

References 34 publications

PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Pitavastatin Prevents Bacterial Translocation after Nonpulsatile/Low-Pressure Blood Flow in Early Atherosclerotic Rat: Inhibition of Small Intestine Inducible Nitric Oxide Synthase

Non-invited Review: Prevention of microvascular diabetic complications by fenofibrate: lessons from FIELD and ACCORD

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