Inhibition of five lipoxygenase activating protein (FLAP) by MK‐886 decreases atherosclerosis in apoE/LDLR‐double knockout mice

Jawień, Jacek; Gajda, Mariusz; Rudling, Mats; Mateuszuk, Łukasz; Olszanecki, Rafał; Guzik, Tomasz J.; Cichocki, T; Chłopicki, Stefan; Korbut, Ryszard

doi:10.1111/j.1365-2362.2006.01606.x

Cited by 92 publications

(76 citation statements)

References 22 publications

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“…Moreover, recent studies in humans and mice have demonstrated that various pharmacological modifiers of the 5-LO pathway decrease inflammatory biomarkers and aortic lesion formation, respectively [9,13,37], raising the possibility of developing 5-LO pathway inhibitors for the treatment of CVD. Our results suggest that it would be important for such therapeutic strategies to carefully consider potentially undesirable metabolic effects.…”

Section: Discussionmentioning

confidence: 99%

“…For example, we demonstrated that deficiency of the gene encoding 5-lipoxygenase (Alox5) in mice protects against the development of aortic lesions [3,4], and that promoter variants of the human ALOX5 gene are associated with increased carotid intima-media thickness [5]. Other groups have also reported findings that support the involvement of the 5-LO/LT pathway in CVD traits [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 88%

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Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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“…Gene-targeted, apolipoprotein E and LDL receptor-double knockout (apoE/LDLR À /À ) mice represent a reliable animal model that displays severe hyperlipidemia and atherosclerosis. We have successively used apoE/LDLR À /À mice to study biological effects of new antiatherosclerotic drugs and diets (Franczyk-Zarow et al, 2008;Jawien et al, 2006). Furthermore, we applied synchrotron radiation microprobes to characterize elemental composition of atherosclerotic lesions in this animal model .…”

Section: Introductionmentioning

confidence: 99%

Distribution of selected elements in atherosclerotic plaques of apoE/LDLR-double knockout mice subjected to dietary and pharmacological treatments

Gajda

Kowalska

Banaś

et al. 2011

Radiation Physics and Chemistry

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a b s t r a c t Gene-targeted, apolipoprotein E and LDL receptor-double knockout (apoE/LDLRÀ / À ) mice represent a new animal model that displays severe hyperlipidemia and atherosclerosis. The aim of the present study was to show changes in histomorphology and in distribution of selected elements in atherosclerotic plaques of apoE/LDLR À / À mice fed egg-rich proatherosclerotic diet (5% egg-yolk lyophilisate) supplemented or not with perindopril (inhibitor of angiotensin converting enzyme; 2 mg/kg b.w.). Synchrotron radiation micro-X-ray fluorescence spectrometry was combined with histological stainings to determine distribution and concentration of trace and essential elements in atherosclerotic lesions. More advanced atherosclerotic lesions expressed by total area occupied by lipids (oil red-O staining) and by macrophages (CD68 immunohistochemistry) were observed in animals fed egg-rich diet. The perindopril treatment attenuated these effects. No significant differences were observed in the number of intimal smooth muscle cells (smooth muscle actin immunohistochemistry). In animals fed egg-rich diet significantly higher concentrations of Ca and significantly lower contents of S, Cl, , Fe, Cu, Zn and Se in atheromas were seen in comparison to chow diet-fed animals. After pharmacological treatment, concentrations of S, Cl, Fe, Cu, Zn and Se showed the tendency to achieve levels like in animals fed normal diet. K level differed only in group treated with perindopril. Concentration of P did not significantly vary in all experimental groups. Perindopril showed its potency to reduce atherosclerosis, as estimated by the size of the atheroma and content of pro-and antiatherogenic elements.

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“…Indeed, the results of our studies showed that the inhibition of FLAP by MK-886 or BAYx1005 can significantly prevent the development of atherosclerosis in genetargeted apoE/LDLR-DKO mice ( Jawien et al, 2006;. Moreover, this study showed that cysteinyl leukotriene receptor blocker montelukast decreases atherosclerosis in apoE/LDLR-double knockout mice (Jawien et al, 2008).…”

Section: Wwwintechopencom Mouse Models Of Experimental Atheroscleromentioning

confidence: 71%

“…In the review published in Nature Medicine hypercholesterolemia and inflammation were described as "partners in crime" (Steinberg, 2002 The inflammatory concept of atherosclerosis has been formulated just in the recent years. However, it is currently an unquestionable achievement of science which also have specific therapeutic implications (Fan & Watanabe, 2003;Libby, 2000;Jawien et al, 2006;Alpert & Thygesen, 2007).…”

Section: The New Experimental Model Of Atherosclerosismentioning

confidence: 99%

Mouse Models of Experimental Atherosclerosis as a Tool for Checking a Putative Anti-Atherogenic Action of Drugs

Jawień¹

2012

Atherogenesis

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Inhibition of five lipoxygenase activating protein (FLAP) by MK‐886 decreases atherosclerosis in apoE/LDLR‐double knockout mice

Abstract: Our results show for the first time that inhibition of FLAP by MK-886 reduces development of atherosclerosis in gene-targeted apoE/LDLR-DKO mice.

Cited by 92 publications

References 22 publications

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Distribution of selected elements in atherosclerotic plaques of apoE/LDLR-double knockout mice subjected to dietary and pharmacological treatments

Mouse Models of Experimental Atherosclerosis as a Tool for Checking a Putative Anti-Atherogenic Action of Drugs

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