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

Calkin, Anna C.; Cooper, Mark E.; Jandeleit‐Dahm, Karin; Allen, Terri J.

doi:10.1007/s00125-005-0102-6

Cited by 71 publications

(57 citation statements)

References 57 publications

(72 reference statements)

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“…Moreover, it may be due to the specific nature of the effect of the treatment on the vessel wall. For example, treatment of diabetic Apoe −/− mice with inhibitors of AGE formation resulted in an attenuation of atherosclerosis in the thoracic and abdominal regions with no effect seen in the aortic arch, whereas treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, postulated to have direct effects on the vessel wall, was associated with most marked effects within the aortic arch [4,31,32].…”

Section: Discussionmentioning

confidence: 99%

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The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

et al. 2008

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Aims/hypothesis We evaluated the anti-atherosclerotic effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, rosuvastatin, and the angiotensin II receptor blocker (ARB), candesartan, alone and in combination, in the streptozotocin-induced diabetic apolipoprotein Edeficient (Apoe −/− ) mouse. Methods Control and streptozotocin-induced diabetic Apoe −/− mice received rosuvastatin (5 mg kg −1 day −1 ), candesartan (2.5 mg kg −1 day −1 ), dual therapy or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent visual quantification. The abundance of proteins was measured using immunohistochemistry. Results Diabetes was associated with a fourfold increase in total plaque area. Rosuvastatin attenuated plaque area in diabetic mice in the absence of lipid-lowering effects. The anti-atherosclerotic effect of rosuvastatin was comparable to that observed with candesartan. A similar beneficial effect was seen with dual therapy, although it was not superior to monotherapy. Rosuvastatin treatment was associated with attenuated accumulation of AGE and AGE receptor (RAGE) in plaques. Similar beneficial effects on markers of oxidative stress were seen with the ARB and statin. Candesartan was more effective at reducing macrophage accumulation and collagen I abundance in plaques compared with rosuvastatin. The combined effect of candesartan and rosuvastatin was superior in reducing macrophage infiltration, monocyte chemoattractant protein-1 level, vascular AGE accumulation and RAGE abundance in the vascular wall. Furthermore, the combination tended to be more effective in reducing smooth muscle cell infiltration and connective tissue growth factor abundance in plaques. Conclusions/interpretation Rosuvastatin has direct antiatherosclerotic effects in diabetic macrovascular disease. These effects are independent of effects on lipids and comparable to the effects observed with candesartan.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, our laboratory has shown that the diabetic Apoe −/− mouse is an excellent model for studying the effects of various agents on diabetes-associated atherosclerosis, particularly agents that influence the haemodynamic and metabolic pathways that are activated in the diabetic state [31,32].…”

Section: Introductionmentioning

confidence: 99%

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

et al. 2008

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“…The PPAR␥ agonists, such as ciglitazone (CZ), are agents that improve glycemic control by increasing insulin sensitivity (5). These agonists also mediate direct antiatherogenic effects in the diabetic vasculature that are independent of their metabolic actions (4). In the pathogenesis of diabetic vasculopathies, such as in glomerulosclerosis, downregulated PPAR␥ expression is associated with matrix accumulation and glomerulonephritis (23,30,39).…”

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confidence: 99%

Ciglitazone, a PPARγ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance

Sen¹,

Rodríguez²,

Tyagi³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Sen U, Rodriguez WE, Tyagi N, Kumar M, Kundu S, Tyagi SC. Ciglitazone, a PPAR␥ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. Am J Physiol Endocrinol Metab 295: E1205-E1212, 2008. First published September 9, 2008 doi:10.1152/ajpendo.90534.2008.-Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPAR␥ agonists such as ciglitazone (CZ) are known to modulate diabetic nephropathy, the role of CZ in diabetes-associated HHcy and renopathy is incompletely defined. We tested the hypothesis that induction of PPAR␥ by CZ decreases tissue Hcy level; this provides a protective role against diabetic nephropathy. C57BL/6J mice were administered alloxan to create diabetes. Mice were grouped to 0, 1, 10, 12, and 16 wk of treatment; only 12-and 16-wk animals received CZ in drinking water after a 10-wk alloxan treatment. In diabetes, PPAR␥ cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPAR␥ mRNA and protein expression and glomerular level of Hcy, whereas plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-wk diabetic induction, followed by hypofiltration at 10 wk, and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady-state increase of RVR in diabetic mice became normal with CZ treatment. CZ ameliorated decrease bioavailability of NO in the diabetic animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1 expression were increased robustly in diabetic mice and normalized with CZ treatment. Interestingly, TIMP-4 expression was opposite to that of TIMP-1 in diabetic and CZ-treated groups. These results suggested that diabetic nephropathy exacerbated glomerular tissue level of Hcy, and this caused further deterioration of glomerulus. CZ, however, protected diabetic nephropathy in part by activating PPAR␥ and clearing glomerular tissue Hcy.peroxisome proliferator-activated receptor-␥; matrix metalloproteinase; tissue inhibitor of metalloproteinases; glomerulosclerosis PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␥ (PPAR␥) is a member of nuclear hormone receptor superfamily of ligandactivated transcription factors. It plays important roles in maintaining glucose and lipid homeostasis (39). The PPAR␥ agonists, such as ciglitazone (CZ), are agents that improve glycemic control by increasing insulin sensitivity (5). These agonists also mediate direct antiatherogenic effects in the diabetic vasculature that are independent of their metabolic actions (4). In the pathogenesis of diabetic vasculopathies, such as in glomerulosclerosis, downregulated PPAR␥ expression is associated with matrix accumulation and glomerulonephritis (23,30,39). Several studies have shown the efficacy of PPAR␥ agonists to ameliorate the progression of glomerulosclerosis (15) and have suggested that PPAR␥ ligands have a direct beneficial renal effect. However, the role...

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“…Accordingly, we have tested a drug known to reduce this cytokine response for its ability to protect against influenza. Here we report that gemfibrozil, a commonly prescribed drug with long-established lipid-lowering properties (18) but only recently recognized as inhibiting the pathways leading to inflammatory cytokine release (3) (and having associated in vivo activity [4]), increases survival in mouse influenza virus infection. Moreover, mortality was reduced in mice when daily treatment was commenced after illness was evident.…”

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Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza

Budd¹,

Alleva²,

Alsharifi

et al. 2007

Antimicrob Agents Chemother

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Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n ‫؍‬ 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n ‫؍‬ 46) (P ‫؍‬ 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.

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

Cited by 71 publications

References 57 publications

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

Ciglitazone, a PPARγ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance

Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza

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