Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

Ghazalpour, Anatole; Wang, Xuping; Lusis, Aldons J.; Mehrabian, Margarete

doi:10.1534/genetics.106.057455

Cited by 33 publications

(31 citation statements)

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“…In previous studies, we reported that 5-LO deficiency dramatically decreases aortic lesion development in two mouse models [3,4] and that humans carrying certain ALOX5 gene variants have increased carotid intima-media thickness [5]. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, multiple lines of evidence support this concept, including biochemical, genetic and pharmacological studies in both mice and humans [2]. 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: 86%

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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: 86%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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“…After 4 weeks, the heart tissue was collected as described (8). Methods for determining arterial calcification, aortic aneurysms, and atherosclerotic lesions, were described (35,36). For further information, see SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Meng

Vera²,

Che³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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119

130

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The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATPbinding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.expression quantitative trait locus ͉ transgenic ͉ positional cloning ͉ osteopontin C haracterized by hydroxyapatite deposition in necrotic myocytes, myocardial calcification is common in specific forms of cardiomyopathy and in myocardial infarction. It has been estimated that Ϸ8% of patients with severe myocardial infarction develop myocardial calcification within 6 years, suggesting a genetic predisposition for postinjury healing and remodeling processes (1). Historically, dystrophic cardiac calcification (DCC) has been considered a spontaneous form of cardiomyopathy in mice, associated with a variety of predisposing factors, but with normal blood levels of calcium and phosphate. Experimentally, it can be reproducibly initiated using a transdiaphragmal freeze-thaw injury or a high-phosphorous (HP) diet (2, 3). Several inbred mouse strains, including C3H/HeJ (C3H) and DBA/2J (DBA), are highly susceptible, whereas many other inbred mouse strains, including C57BL/6J (B6), C57BL/10J (B10), A/J, MRL/MpJ, and BALB/cJ are resistant (refs. 4 and 5; X.W., T.A.D., and A.J.L., unpublished data). In DCC susceptible strains, calcification has also been observed in skeletal muscle, including in the tongue and diaphragm, and kidney, suggesting a systemic defect (2, 5).Using quantitative trait locus (QTL) analysis of an F 2 intercross between B6 and C3H mice (BxH), we previously mapped four DCC loci (6, 7). The locus on chromosome 7 (Dyscalc1), which exhibits recessive inheritance, explains 31% of the total genetic variance and is the major contributor. Dyscalc1 was confirmed by separate intercrosses of B6 and DBA mice (BxD) (5, 8). The C3H strain was originally derived from an outbreeding experiment of the DBA strain, leading us to hypothesize that the susceptible strains C3H and DBA share a common diseasecausing allele (8). To fine map the Dyscalc1 locus, we screened a panel of recombinant congenic (RC) s...

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“…These animals that did not survive well on the atherosclerotic diet given with only heterozygote 5-LO Ϯ mice surviving (1181). Mice in that study appeared to have been derived from congenic strain that had potentially many other differences in genes immediately surrounding 5-LO (611,1180). A relatively specific inhibitor of 5-LO was recently reported to reduce atherosclerosis in LDLR-null by 43% (315).…”

Section: Sphingolipid and Eicosanoid Signaling In Macrophagesmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

Cited by 33 publications

References 58 publications

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Molecular Biology of Atherosclerosis

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