Angiopoietin-2 Confers Atheroprotection in apoE
            <sup>−/−</sup>
            Mice by Inhibiting LDL Oxidation via Nitric Oxide

Ahmed, Asif; Fujisawa, Takeshi; Niu, Xi-Lin; Ahmad, Shakil; Al‐Ani, Bahjat; Chudasama, Kunal; Abbas, A.S.; Potluri, Rahul; Bhandari, Vineet; Findley, Clarence M.; Lam, Gregory K.W.; Huang, Jianhua; Hewett, Peter W.; Cudmore, Melissa; Kontos, Christopher D.

doi:10.1161/circresaha.109.196154

Cited by 43 publications

(38 citation statements)

References 17 publications

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“…Our present results showed that 1 major mechanism underlying the protective effect of TrkB on CAD may be through promoting endothelial barrier's integrity. Similarly, as an angiogenic factor, angiopoietin-1 14 and angiopoietin-2 15 have been reported to protect adult vasculature integrity against atherosclerosis. TrkB has also been found in smooth muscle cell of advanced atherosclerotic lesions and to promote smooth muscle cell activity.…”

Section: Discussionmentioning

confidence: 97%

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Jiang

Huang

et al. 2015

ATVB

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Objective-Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor. In addition to its nervous system functions, TrkB is also expressed in the cardiovascular system. However, the association of TrkB and coronary artery disease (CAD) remains unknown. We investigated the role of TrkB in the development of CAD and its mechanism. Approach and Results-We performed a case-control study in 2 independent cohort of Chinese subjects and found -69C>G polymorphisms of TrkB gene significantly associated with CAD. TrkB -69C homozygotes, which corresponded to decreased TrkB expression by luciferase reporter assay, showed increased risk for CAD. Immunofluorescence analysis revealed that TrkB was expressed in the aortic endothelium in atherosclerotic lesions in humans and ApoE -/-mice. TrkB knockdown in the aortic endothelium resulted in vascular leakage in ApoE -/-mice. Mechanistic studies showed that TrkB regulated vascular endothelial cadherin (VE-cadherin) expression through induction and activation of Ets1 transcriptional factor. Importantly, TrkB activation attenuated proatherosclerotic factors induced-endothelial hyperpermeability in human vascular endothelial cells.Conclusions-Our data demonstrate that TrkB protects endothelial integrity during atherogenesis by promoting Ets1-mediated VE-cadherin expression and plays a previously unknown protective role in the development of CAD. Table). This difference was also observed in the Shanxi group (all P<0.05; Table). Multiple logistic regression analysis revealed homozygous TrkB -69C, rather than TrkB -69G carriers, were associated with an increased risk of CAD in the Shandong group (odds ratio, 2.1; 95% confidence interval, 1.68-2.62; P<0.01) and in the Shanxi group (odds ratio, 2.0; 95% confidence interval, 1.69-2.67; P<0.01), after adjusting sex, age, and body mass index. There was no association between the TrkB IVS13+40G>A polymorphism and CAD (P>0.05; Table). All genotype frequencies showed Hardy-Weinberg equilibrium. Statistical powers are all 100% in Shandong and Shanxi group. The clinical characteristics of the 2 cohorts of patients and controls are shown in Table I in the online-only Data Supplement.Polymorphism -69C>G is located in the promoter region of TrkB. It has been reported that approximately one third of promoter variants may alter gene expression to a functionally relevant extent. 8 We then constructed luciferase reporter vectors with TrkB promoter segments (-3258 to -11 bp) of contrasting genotypes (-69CC versus -69GG; Figure 1A and 1B) and tested the effect of TrkB -69C>G polymorphism on luciferase reporter gene expression. Regardless of genotype, the promoter significantly promoted luciferase expression ( Figure 1C and 1D). Of note, luciferase activity was significantly lower with the -69C construct than with the -69G construct in HeLa cells and human vascular endothelial cells (ECs; Figure 1C and 1D). These data suggested that decreased TrkB expression might be associated with increased risk for CAD. TrkB is...

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Section: Discussionmentioning

confidence: 97%

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Jiang

Huang

et al. 2015

ATVB

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“…12 In the literature, Ang-2 signaling in vivo has been studied intensively, however, mainly by overexpression in tumor cells 22 or using adenoviruses leading to widespread cellular expression. [23][24][25][26][27] In the genetic model used within this study, Ang-2 expression is predominant in the vasculature, the physiologic site of Ang-2 expression, and as such provides an excellent tool to investigate angiopoietin signaling in vivo. .…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin–dependent manner

Scholz

Lang

Henschler

et al. 2011

Blood

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In human inflammatory diseases, we identified endothelial angiopoietin-2 (Ang-2) expression to be strongly associated with inflammations mediated by myeloid cells but not lymphocytes. To identify the underlying mechanism, we made use of a transgenic mouse model with inducible endothelial cell-specific expression of Ang-2. In this model, in the absence of inflammatory stimuli, long-term expression of Ang-2 led to a time-dependent accumulation of myeloid cells in numerous organs, suggesting that Ang-2 is sufficient to recruit myeloid cells. In models of acute inflammation, such as delayed-type hypersensitivity and peritonitis, Ang-2 transgenic animals showed an increased responsiveness. Intravital fluorescence video microscopy revealed augmented cell adhesion as an underlying event. Consequently, we demonstrated that Ang-2 is able to induce strong monocyte adhesion under shear in vitro, which could be blocked by antibodies to ␤ 2 -integrin. Taken together, our results describe Ang-2 as a novel, endothelialderived regulator of myeloid cell infiltration that modulates ␤ 2 -integrinmediated adhesion in a paracrine manner. (Blood. 2011;118(18):5050-5059)

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“…Nuclear FoxO1 also induces endothelial ICAM-1 and TNF-␣ expression in LDLR-deficient mice. Surprisingly, however, adenoviral overexpression of ANGPT2 in ApoE KO mice was atheroprotective, apparently through increased PKB and eNOS activity (20), while overexpression of ANGPT1 increased atherosclerosis in these mice, possibly by activation of leukocyte Tie2 (19). The interpretation of these results is complicated by potential differences in outcomes when angiopoietins are induced by adenoviral-induced overexpression versus more physiological levels.…”

Section: Endothelial Quiescence Through Tie2 Signalingmentioning

confidence: 92%

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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Angiopoietin-2 Confers Atheroprotection in apoE ^−/− Mice by Inhibiting LDL Oxidation via Nitric Oxide

Cited by 43 publications

References 17 publications

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin–dependent manner

Molecular Biology of Atherosclerosis

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Angiopoietin-2 Confers Atheroprotection in apoE −/− Mice by Inhibiting LDL Oxidation via Nitric Oxide

Cited by 43 publications

References 17 publications

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin–dependent manner

Molecular Biology of Atherosclerosis

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Angiopoietin-2 Confers Atheroprotection in apoE ^−/− Mice by Inhibiting LDL Oxidation via Nitric Oxide