No association of two functional polymorphisms in human ALOX15 with myocardial infarction

Hersberger, Martin; Müller, Martina; Marti-Jaun, Jacqueline; Heid, Iris M.; Coassin, Stefan; Young, Thomas M.; Waechter, Vanessa; Hengstenberg, Christian; Meisinger, Christa; Peters, Annette; König, Wolfgang; Holmer, Stephan; Schunkert, Heribert; Klopp, Norman; Kronenberg, Florian; Illig, Thomas

doi:10.1016/j.atherosclerosis.2008.11.017

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…In both studies, homozygote carriers were too rare to draw conclusions. In an independent large scale (some 2600 participants) case control study (20), a similar trend toward an increased risk for myocardial infarction was observed for heterozygote allele carriers of the T560M mutation (odd ratio, 1.7; p ϭ 0.06).…”

Section: Lipoxygenases (Loxs)mentioning

confidence: 64%

“…The molecular basis for this effect remains unclear, but involvement of ALOX15 in vasodilatation was discussed as a possible reason in one of these studies (20). However, because the T560M SNP is very rare in Caucasians (less than 1% heterozygous allele carriers), both studies were underpowered to draw definite conclusions on the pathophysiological relevance of this SNP in myocardial infarction and/or coronary artery disease.…”

Section: Lox Speciesmentioning

confidence: 99%

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Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease

Schurmann

Anton

Ivanov

et al. 2011

Journal of Biological Chemistry

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Lipoxygenases have been implicated in cardiovascular disease. A rare single-nucleotide polymorphism causing T560M exchange has recently been described, and this mutation leads to a near null variant of the enzyme encoded for by the ALOX15 gene. When we inspected the three-dimensional structure of the rabbit ortholog, we localized Thr-560 outside the active site and identified a hydrogen bridge between its side chain and Gln-294. This interaction is part of a complex hydrogen bond network that appears to be conserved in other mammalian lipoxygenases. Gln-294 and Asn-287 are key amino acids in this network, and we hypothesized that disturbance of this hydrogen bond system causes the low activity of the T560M mutant. To test this hypothesis, we first mutated Thr-560 to amino acids not capable of forming side chain hydrogen bridges (T560M and T560A) and obtained enzyme variants with strongly reduced catalytic activity. In contrast, enzymatic activity was retained after T560S exchange. Enzyme variants with strongly reduced activity were also obtained when we mutated Gln-294 (binding partner of Thr-560) and Asn-287 (binding partner of Gln-294 and Met-418) to Leu. Basic kinetic characterization of the T560M mutant indicated that the enzyme lacks a kinetic lag phase but is rapidly inactivated. These data suggest that the low catalytic efficiency of the naturally occurring T560M mutant is caused by alterations of a hydrogen bond network interconnecting this residue with active site constituents. Disturbance of this bonding network increases the susceptibility of the enzyme for suicidal inactivation.

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Section: Lipoxygenases (Loxs)mentioning

confidence: 64%

Section: Lox Speciesmentioning

confidence: 99%

Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease

Schurmann

Anton

Ivanov

et al. 2011

Journal of Biological Chemistry

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“…The few clinical epidemiological human studies to date all support an anti-atherogenic or at least neutral role for 12/15-LOX downstream actions [38,39,40], data that support findings in transgenic rabbits that overexpress 12/15-LOX as well as in regular chow-fed mouse models that under- and overexpress the enzyme. Nonetheless, LOXs have displayed intriguing nutrigenetic associations with cardiovascular diseases in human populations and with the metabolic syndrome in mice [41,42].…”

Section: Discussionmentioning

confidence: 53%

Nutrigenetic Disruption of Inflammation-Resolution Homeostasis and Atherogenesis

Merched

Serhan

2011

Lifestyle Genomics

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Background/Aim: Pro-resolving and anti-inflammatory mediator products of murine 12/15-lipoxygenase (LOX) exhibit potent actions on vascular inflammation and protect against the progression of atherosclerosis. The present study was designed to determine whether augmenting dietary lipids modulates the body’s endogenous anti-inflammatory pro-resolving mechanisms and promotes atherosclerosis. Methods/Results: We investigated the biometabolic consequences of variations in lipid mediator biosynthesis using genetic knockout and overexpression models of 12/15-LOX mice fed the commonly used ‘Western diet’. Unexpectedly, this high-fat diet annulled the protective actions of 12/15-LOX, and the combination of a Western diet and 12/15-LOX overexpression paradoxically promoted inflammation leading to production of diet-related and 12/15-LOX-dependent blood mediators that differentially activated endothelial cells via expression of ICAM-1. Hyperlipidemia not only affected the biosynthesis of lipoxin A₄, a key pro-resolving mediator, but also disrupted the protective pro-resolving function of 12/15-LOX products, and the enzyme pathway no longer protected against atherosclerosis in vivo. Conclusion: We uncovered a novel mechanism whereby a high-fat diet as well as hyperlipidemia disrupt the homeostasis of inflammation resolution. These findings underscore the importance of dietary essential PUFAs and LOX-derived lipid mediators in combination with lipid-lowering agents in the prevention and treatment of atherosclerotic cardiovascular diseases.

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“…Thus far, all large study samples from Caucasians investigating the association of the inactivating polymorphism (T560M) in 15-lipoxygenase showed a similar risk increase. However, this was found not to be significant in two of the studies because of the low frequency of the T560M polymorphism (136,138). Taken together, the role of the 15-lipoxygenase enzyme in human atherosclerosis has not yet been solved, although there is currently more support for a neutral or atheroprotective role for 15-lipoxygenase in human disease, than for promoting atherosclerosis.…”

Section: Role Of the 12-and 15-lipoxygenase Pathways In Atherosclerosismentioning

confidence: 90%

“…These results indicate that ALOX15 may be anti-inflammatory and anti-atherogenic in humans. However, corroboration of such an atheroprotective effect of the 15-lipoxygenase gene was unsuccessful in a recent large case control study, the MONIKA/KORA cohort which investigated the effect of these polymorphisms on myocardial infarction (138). In this study, the activating c.-292C)T polymorphism showed no effect on the risk for myocardial infarction, while the inactivating T560M polymorphism showed a trend for an association with myocardial infarction, with a similar risk increase (OR 1.7) as reported in the ADVANCE study (136).…”

Section: Role Of the 12-and 15-lipoxygenase Pathways In Atherosclerosismentioning

confidence: 99%

Potential role of the lipoxygenase derived lipid mediators in atherosclerosis: leukotrienes, lipoxins and resolvins

Hersberger

2010

Clinical Chemistry and Laboratory Medicine

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Atherogenesis is an inflammatory process with leukocytes infiltrating the arterial intima. The lipoxygenase pathways play a role in leukocyte recruitment through the generation of two classes of arachidonic acid lipid mediators, the leukotrienes and the lipoxins, and one class of omega-3 fatty acid metabolites, the resolvins. There is evidence from animal studies and human genetic studies that the leukotrienes and the enzymes necessary for their generation play a role in atherosclerosis, and possibly even in the development of the vulnerable plaque. Less is known about the effect of the anti-inflammatory lipid mediators in atherosclerosis, the lipoxins and the resolvins. Studies modulating the activity of an enzyme necessary for the production of these lipid mediators, 12/15-lipoxygenase, showed discrepant results in several animal models. Also, human genetic studies have not clearly dissected the effect of the enzyme on atherosclerosis. However, stable forms of the lipoxins and the resolvins protect animals from inflammatory diseases. Whether blocking the leukotrienes or applying anti-inflammatory lipoxins and resolvins will be effective in attenuating human atherosclerosis needs to be demonstrated in future studies. In this review, the biosynthesis of these lipid mediators, their biological effects and the evidence for their possible role in atherosclerosis are discussed with an emphasis on human disease.

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No association of two functional polymorphisms in human ALOX15 with myocardial infarction

Cited by 16 publications

References 27 publications

Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease

Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease

Nutrigenetic Disruption of Inflammation-Resolution Homeostasis and Atherogenesis

Potential role of the lipoxygenase derived lipid mediators in atherosclerosis: leukotrienes, lipoxins and resolvins

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