In vivo action of 15-lipoxygenase in early stages of human atherogenesis.

Kühn, Hartmut; Heydeck, Dagmar; Hugou, Isabelle; Gniwotta, Christina

doi:10.1172/jci119253

Cited by 156 publications

(97 citation statements)

References 33 publications

(36 reference statements)

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“…We propose that enzymatic degradation rather than oxidation is the central event underlying transformation of LDL to a proinflammatory moiety. This would explain why oxidatively modified lipids are hardly detectable in early lesions, 54 why subendothelially deposited LDL is morphologically altered, 9,35,38 -40 and why complement activation occurs at an early stage. 7 Our concept obviates the need to seek for extraneous factors, such as oxidation or infection, to drive the pathological process.…”

Section: Discussionmentioning

confidence: 99%

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Schmiedt

Kinscherf

Deigner

et al. 1998

ATVB

120

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Abstract-Low-density lipoprotein (LDL) can be transformed to an atherogenic moiety by nonoxidative, enzymatic degradation. Enzymatically degraded LDL induces macrophage foam cell formation, provokes release of cytokines, and also activates complement. To determine whether complement activation may contribute to atherogenesis, 6 pairs of homozygous C6-deficient rabbits and their non-C6-deficient heterozygous siblings were fed a cholesterol-rich diet for 14 weeks. Cholesterol levels and plasma lipoprotein profiles of the animals in the C6-competent and C6-deficient groups did not significantly differ, and the high density lipoprotein and LDL cholesterol ratios at the end of the experiment were 0.07Ϯ0.01 and 0.08Ϯ0.01 (SEM), respectively. However, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all C6-competent animals and absent in all C6-deficient animals. Aortas were sectioned from thorax to abdomen, and 10 sections were stained from each aorta. Quantification of atherosclerotic lesions and lumen stenosis with the use of computer-based morphometry documented a dramatic protective effect of C6 deficiency on the development of diet-induced atherosclerosis. We conclude that the terminal complement sequence is centrally involved in atherosclerotic lesion progression. (Arterioscler Thromb Vasc Biol. 1998;18:1790-1795.)Key Words: complement activation Ⅲ atherosclerosis T he possible relevance of complement activation in atherogenesis has not received much attention to date, and only a few reviews are available on the topic. 1,2 The first immunohistochemical studies on complement deposition in atherosclerotic lesions appeared in 1985 to 1987, 3-5 and C5b-9 complexes were subsequently quantified by ELISA in detergent extracts of lesion homogenates. 6 In those studies, the stages of lesion development were not defined, so it could not be excluded that complement activation might have occurred subsequent to tissue damage. An experimental study was then performed in rabbits, leading to the clear demonstration that diet-induced deposition of lipids in the subendothelium was temporally associated with complement activation, which occurred before lesion infiltration by monocytes. 7 A directed search led to tentative identification of the complement-activating entity. Heterogeneously sized lipid droplets containing high amounts of free cholesterol were isolated from early lesions and were shown to be capable of spontaneously activating the alternative complement pathway. 8 The origin of this lipid, termed the lesion complement activator (LCA), was unknown, but the possibility that it represented an LDL derivative was obvious. To corroborate this assumption, attempts were undertaken to transform LDL in vitro into a complement-activating moiety. This was found to be possible by combined treatment of the lipoprotein with a protease, cholesterol-esterase, and neuraminidase, 9 enzymes that occur ubiquitously in lysosomes of mammalian cells and that are...

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Section: Discussionmentioning

confidence: 99%

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Schmiedt

Kinscherf

Deigner

et al. 1998

ATVB

120

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“…The possible role of ALOX15 in cardiovascular diseases has been a matter of discussion for many years (9,10) and pro-and anti-atherogenic (11)(12)(13) activities have been reported in various animal atherosclerosis models. In humans, expression of ALOX15 has been detected in atherosclerotic lesions (14), and structural analysis of deposited lipids suggested its catalytic activity in young human plaques (15). On the other hand, more recent studies failed to detect significant amounts of ALOX15 mRNA in advanced human lesions (16) but suggested significantly higher levels of ALOX5 transcripts.…”

Section: Lipoxygenases (Loxs)mentioning

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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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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“…Furthermore, indirect evidence for 15-LO activity has been found in early atherosclerotic lesions from humans supporting its pro-atherogenic role [37]. However, it has also to be noted that some metabolites of the 12/15-LO system seem to have anti-inflammatory effects, e.g.…”

Section: /15-lipoxygenase (12/15-lo) Pathwaymentioning

confidence: 99%

Mechanisms by which diabetes increases cardiovascular disease

Gleissner

Galkina

Nadler

et al. 2007

Drug Discovery Today: Disease Mechanisms

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Diabetes mellitus is one of the major risk factors for cardiovascular disease which is the leading cause of death in the U.S. Increasing prevalence of diabetes and diabetic atherosclerosis makes identification of molecular mechanisms by which diabetes promotes atherogenesis an important task. Targeting common pathways may ameliorate both diseases. This review focuses on well known as well as newly discovered mechanisms which may represent promising therapeutic targets.

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In vivo action of 15-lipoxygenase in early stages of human atherogenesis.

Cited by 156 publications

References 33 publications

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

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

Mechanisms by which diabetes increases cardiovascular disease

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