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

Huo, Yuqing; Zhao, Lei; Hyman, Matthew C.; Shashkin, Pavel; Harry, Brian L.; Burcin, Tracy L.; Forlow, S. Bradley; Stark, Matthew A.; Dl, Smith; Clarke, Sean P.; Srinivasan, Suseela; Hedrick, Catherine C.; Praticò, Domenico; Witztum, Joseph L.; Nadler, Jerry L.; Funk, Colin D.; Ley, Klaus

doi:10.1161/01.cir.0000143628.37680.f6

Cited by 181 publications

(143 citation statements)

References 41 publications

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“…31,34 Indeed, disruption of the 12/15LO gene diminished atherosclerosis in ApoE Ϫ/Ϫ mice, 35 and macrophage 12/15LO has been implicated in this effect. 36 Results of the present study demonstrate that in addition to reduced atherosclerosis, DKO mice have attenuated NIF in response to injury. Although loss of 12/15LO in macrophages may have contributed to the attenuated response to injury in DKO mice, our findings that cultured VSMCs from DKO mice have attenuated proliferation compared with ApoE Ϫ/Ϫ controls suggest that reduced VSMC proliferation may be an additional mechanism contributing to attenuated NIF in DKO mice.…”

Section: Discussionsupporting

confidence: 55%

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

Deliri

Meller

Kadakkal

et al. 2011

ATVB

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Objective-To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. Methods and Results-12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E Ϫ/Ϫ , ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ , C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE Ϫ/Ϫ VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21 cip1 promoter and abrogated 12/15LO-induced VSMC proliferation. Conclusion-To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Key Words: vascular biology Ⅲ fibronectin Ⅲ helix-loop-helix motifs Ⅲ lipoxygenase Ⅲ neointima Ⅲ smooth muscle cell I ndividuals with type 2 diabetes mellitus have increased rates of restenosis after vascular interventional procedures. 1,2 Vascular smooth muscle cell (VSMC) proliferation and matrix production are key events in the process of neointimal formation (NIF) after percutaneous interventions. 3,4 Identifying the molecular mechanisms that mediate acceleration of these processes may provide important insight into strategies to attenuate restenosis in high-risk populations, such as those with type 2 diabetes.Previous studies have implicated 12/15-lipoxygenase (12/ 15LO) in the vascular response to injury. 12/15LO products of arachidonic acid, such as 12S-hydroxyeicosatetrenoic acid (HETE), 15S-HETE, and 13S-hydroperoxyoctadecadienoic acid (HPODE), are produced in VSMCs and have hypertrophic effects. 5,6 In vitro, 12/15LO inhibition attenuates hypertrophic effects of angiotensin II in VSMCs, mitogenic effects of cytokines, and chemotactic effects of platelet-derived growth factor. 5,7,8 Compared with VSMCs from C57BL/6 (BL-6) mice, VSMCs from 12/15LO-overexpressing transgenic (12/15LO-tg) mice grow faster, and VSMCs from 12/15LO Ϫ/Ϫ mice grow slower and display decreased S-phase entry in culture. 9,10 12/15LO and its products are increased in the vascular wall of animal models of atherosclerosis and injury-induced restenosis. 11 Compared with uninjured carotids, 12/15LO expression is significantly increased in rat carotids on day 12 after injury. 12 Moreover, pharmacological...

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Section: Discussionsupporting

confidence: 55%

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

Deliri

Meller

Kadakkal

et al. 2011

ATVB

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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).…”

mentioning

confidence: 99%

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

Krönke

Katzenbeisser

Uderhardt

et al. 2009

The Journal of Immunology

138

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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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“…We previously examined the contribution of macrophage versus endothelial-derived 12/15LO eicosanoids as critical mediators of atherogenesis in apoE-deficient mice in vivo. 40 We found that presence of 12/15LO in bone marrow-derived cells was critical for atherogenesis. 40 However, we could not rule out contribution of endothelial 12/15LO in this process.…”

mentioning

confidence: 84%

“…40 We found that presence of 12/15LO in bone marrow-derived cells was critical for atherogenesis. 40 However, we could not rule out contribution of endothelial 12/15LO in this process. Thus, we conclude that 12/15LO products, either monocytederived or endothelial-derived, can activate an endothelial surface receptor to cause endothelial activation via a rhoA/ NF-B signaling cascade.…”

mentioning

confidence: 84%

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

Abstract: Background-Mice

Cited by 181 publications

References 41 publications

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

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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