Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial

Hákonarson, Hákon; Thorvaldsson, Sverrir; Helgadóttir, Anna

doi:10.1016/j.accreview.2005.08.001

Cited by 51 publications

(62 citation statements)

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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%

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%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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“…Furthermore, short time treatment with the LT synthesis inhibitor BAYx1005/DG031 (Fig. 1) has been evaluated in both COPD and in patients with a history of myocardial infarction [15,16]. Although the treatment protocols used in both the latter two studies resulted in only modest inhibition of LTB 4 concentrations in either sputum or stimulated whole blood, the results suggested a tendency for decrease of inflammatory markers [15,16].…”

Section: Proinflammatory Leukotriene Signaling In Atherosclerosismentioning

confidence: 92%

“…1) has been evaluated in both COPD and in patients with a history of myocardial infarction [15,16]. Although the treatment protocols used in both the latter two studies resulted in only modest inhibition of LTB 4 concentrations in either sputum or stimulated whole blood, the results suggested a tendency for decrease of inflammatory markers [15,16]. Despite the limitations (small patient numbers, short time treatments, limited LT inhibition etc), these studies provide an initial suggestion as to a potential beneficial effect of an anti-LT treatment in atherosclerosis.…”

Section: Proinflammatory Leukotriene Signaling In Atherosclerosismentioning

confidence: 99%

Leukotriene Signaling in Atherosclerosis and Ischemia

Bäck

2008

Cardiovasc Drugs Ther

121

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“…On the basis of this finding, drugs to inhibit the 5-lipoxygenase-activating protein have been developed, and the first trial studied only patients selected for the at-risk genetic variant (60). This study paradigm shows how screening very large gene sets, up to the whole genome, can inform new biology and drug development, an advantage that the candidate gene approach generally lacks.…”

Section: Disease Phenotypesmentioning

confidence: 99%