The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm

Zhao, Lei; Moos, Michael; Gräbner, Rolf; Pédrono, Frédérique; Fan, Jinjin; Kaiser, Brigitte; John, Nicole; Schmidt, Sandra; Spanbroek, Rainer; Lötzer, Katharina; Huang, Li; Cui, Jisong; Rader, Daniel J.; Evans, Jilly F.; Habenicht, Andreas J. R.; Funk, Colin D.

doi:10.1038/nm1099

Cited by 315 publications

(310 citation statements)

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“…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%

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: Introductionmentioning

confidence: 88%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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“…In a cholate diet-triggered model of AAA, 5-LO deficiency strikingly diminished aneurysmal dilation in a hyperlipidemic mouse background (10). The study demonstrated that 5-LO ϩ macrophages localize to the adventitia of diseased mouse arteries and constitute a main component of aortic aneurysms.…”

Section: Discussionmentioning

confidence: 74%

“…Thus, deletion of BLT1 appears to prevent leukotriene-induced increases in vascular wall MCP-1 expression in vivo. Zhao et al (10) found that 5-LO deficiency significantly attenuates plasma MIP-1␣, another monocyte chemoattractant associated with vascular pathology. We found a marked reduction in MIP-1␣ in the suprarenal aortas of Ang II-treated Apoe Ϫ/Ϫ / Blt1 Ϫ/Ϫ mice as compared with those from the Ang II-treated Apoe Ϫ/Ϫ controls consistent with this prior study (Fig.…”

Section: Decreased Proinflammatory Cytokine Levels In Apoementioning

confidence: 99%

Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice

Ahluwalia

Lin

Tager

et al. 2007

The Journal of Immunology

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Leukotriene B4 is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A4 hydrolase. Leukotriene B4 signals primarily through its high-affinity G protein-coupled receptor, BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. In this study, we tested the hypothesis that BLT1 is necessary for abdominal aortic aneurysm (AAA) formation, a major complication of atherosclerotic vascular disease. Chow-fed Apoe−/− and Apoe−/−/Blt1−/− mice were treated with a 4-wk infusion of angiotensin II (1000 ng/min/kg) beginning at 20 wk of age, in a well-established murine AAA model. We found a reduced incidence of AAA formation as well as concordant reductions in the maximum suprarenal/infrarenal diameter and total suprarenal/infrarenal area in the angiotensin II-treated Apoe−/−/Blt1−/− mice as compared with the Apoe−/− controls. Diminished AAA formation in BLT1-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, we have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. These findings extend the role of BLT1 to a critical complication of vascular disease and underscore its potential as a target for intervention in modulating multiple pathologies related to atherosclerosis.

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“…5 Modifier genes such as 5,10-methylenetetrahydrofolate reductase (MTHFR) help to identify patients who have a high probability of developing severe manifestations of the disease. 8 Susceptibility genes, such as MTHFR, 9 metalloproteinase-9, 10 chemokine receptor 5 (CCR5) 11 5-lipoxygenase (5-LO), 12 carrying polymorphic mutations such as C677T MTHFR, C1562T MMP9, ∆32 CCR5, [11][12][13] predispose to abdominal aortic aneurysms (AAA) and/or atherosclerosis.…”

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confidence: 99%

“…In addition, Hcy may directly affect fibrillin-1 or collagen by interfering with intra-and/or intermolecular disulfide bonds through disulfide exchange, or binding to free sulphydryl groups. If the usefulness of including Hcy determination in the clinical evaluation is confirmed, it will be possible to identify the potential candidates for a vitamin supplementation using folic acid, or vitamins B 6 or B 12 .…”

mentioning

confidence: 99%