Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.

Shen, Jianhe; Herderick, E E; Cornhill, J. Fredrick; Zsigmond, Eva M; Kim, Han Seob; Kühn, Hartmut; Guevara, J.; Chan, Lawrence

doi:10.1172/jci119029

Cited by 216 publications

(131 citation statements)

References 34 publications

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“…The BMT study suggests that macrophage 12/15-LO is proatherogenic in mice. This is inconsistent with previous studies by Shen et al, 17 who found that 15-LO in monocytes/macrophages is antiatherogenic in a rabbit atherosclerotic model. The conflicting conclusions from these studies may be due to differences in species (rabbit versus mouse), lipoxygenase gene products (ratio of 12HETE:15HETE), and genetic manipulation (knockout versus transgenic overexpression).…”

Section: Discussioncontrasting

confidence: 99%

“…10 -12 A variety of vascular cells are able to express 12/15-LO, including endothelial cells, 13,14 smooth muscle cells, 13,14 and monocytes/macrophages. 13,15 Overexpression of 12/15-LO in mouse endothelial cells 16 and rabbit monocytes/macrophages 17 resulted in completely opposite effects: The former was proatherogenic and the latter antiatherogenic, which indicates a possibility that different cellular expression of 12/15-LO may have different effects on atherosclerosis or that species differences may exist.…”

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confidence: 99%

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Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

et al. 2004

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

et al. 2004

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“…Importantly, this enzyme displays additional properties, including the oxidation of low-density lipoproteins (10), allowing it to contribute to vascular inflammation and development of atherosclerosis (11)(12)(13)(14). Hence, and despite the potential anti-inflammatory action of 12/15-LO, animal models studying the role of 12/15-LO in the pathogenesis of atherosclerosis delivered conflicting results (15)(16)(17)(18)(19).…”

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confidence: 99%

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Krönke

Katzenbeisser

Uderhardt

et al. 2009

The Journal of Immunology

139

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Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A4 (LXA4). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA4 within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA4, which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-α. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis.

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“…15SHETE can serve as a substrate for 5-LO to generate anti-inflammatory lipoxins, [41][42][43] and can also serve as a ligand for the nuclear hormone receptor PPAR␥. 44,45 Two studies in transgenic rabbits that overexpressed human 15-LO indicated that 15-LO expression reduced atherosclerosis development, 46,47 whereas 2 other studies indicated that treatment of rabbits with 15-LO inhibitors reduced atherosclerosis progression. 48,49 Although murine 12/15LO has been shown to mediate atherosclerosis development in mouse models of atherosclerosis, the exact mechanisms through which this occurs are unclear.…”

Section: Discussionmentioning

confidence: 99%

12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E–Deficient Mice Through Activation of RhoA and NF-κB

Bolick

Srinivasan

Whetzel

et al. 2006

ATVB

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Objectives-12/15 lipoxygenase (12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte:endothelial interactions in vivo in apolipoprotein E-deficient mice (apoEKO), a well-characterized mouse model of atherosclerosis. Methods and Results-In apoEKO mice that are also deficient in 12/15LO (doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC (Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-B. DoubleKO aorta displayed little nuclear localization of NF-B. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKC␣ significantly reduced NF-B activation, ICAM-1 induction, and monocyte adhesion to aorta. A key early event in atherosclerosis development is the interaction of monocytes and endothelial cells in the vessel wall. 1 Activated monocytes interact with selectins, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cell surface to roll along and firmly adhere to the endothelium. 2,3 Monocytes are the primary inflammatory cells localized to human atherosclerotic plaques and play a major role in atherosclerotic plaque progression. 4 The apolipoprotein E-deficient mouse (apoEKO) is a well-characterized model of atherosclerosis that develops extensive aortic and coronary atherosclerosis and severe hypercholesterolemia when fed a Western-type diet. 5,6 Studies have reported increased Pselectin-mediated and VCAM-1-mediated monocyte rolling along apoE-deficient mouse endothelium, 7,8 and have illustrated that VCAM-1 and ICAM-1 are critical for atherosclerosis development in apoEKO mice. 9,10 See page 1204 12/15 lipoxygenase (12/15LO) incorporates molecular oxygen in a stereo-specific manner into arachidonic and linoleic acids to generate 12-S-and 15-S-hydroxyeicosatetraenoic acids (12SHETE/15SHETE) and 13-Shydroxyoctadecadienoic acid (13SHODE), respectively. 11,12 Sources of 12/15LO eicosanoids in vascular cells are endothelial cells, smooth muscle cells, monocytes, and platelets. 13 Several groups have shown that the human 12/15LO enzyme oxidizes low-density lipoprotein (LDL) in vitro, and that 12/15LO inhibitors decrease the ability of macrophages to oxidize LDL. 14 -17 12/15LO protein has been localized to aortic atherosclerotic lesions in rabbits and in humans. 18,19 We have shown that activated human endothelial cells (ECs) have increased expression of 12/ 15LO protein that mediates monocyte adhesion. 20 We have also shown that exogenous addition of 12SHETE and 15SHETE to EC significantly ...

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Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.

Cited by 216 publications

References 34 publications

Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E–Deficient Mice Through Activation of RhoA and NF-κB

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