Regulation of Vulnerable Plaque Development by the Heme Oxygenase/Carbon Monoxide System

Larsen, Katarina; Cheng, Caroline; Duckers, Henricus J.

doi:10.1016/j.tcm.2010.04.001

Cited by 9 publications

(7 citation statements)

References 81 publications

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“…27,28 Ets2 silencing also inhibited expression of EphrinB2, EphB4, Jagged1, and DLL4. Both DLL4/Jagged1/notch1/4 and EphrinB2/EphB4 signaling are vital regulatory pathways for angiogenesis.…”

Section: Cheng Et Almentioning

confidence: 90%

Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions

Cheng

Tempel

Dekker

et al. 2011

Circulation Research

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Rationale: Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarrayscreen of Flk1؉ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor. Objectives:We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. Methods and Results:In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-␣ (TNF␣), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE ؊/؊ mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNF␣. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNF␣-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNF␣-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ endothelium Ⅲ vascular inflammation Ⅲ vulnerable plaque A therosclerosis is a complex disease with a strong inflammatory component, [1][2][3][4] initially triggered by endothelial dysfunction and characterized by an influx of atherogenic lipoprotein components, combined with endothelial upregulation of proinflammatory cytokines and adhesion molecules. 5 Monocyte adhesion and extravasation perpetuate the disease by further differentiation into macrophages and foam cells, ultimately driving atherosclerotic lesion growth and complexity. 6 Vulnerable plaque (VP) is an advanced form of atherosclerosis, characterized by an exuberated inflammatory response with the formation of a large necrotic core, and a rupture-prone thin fibrous cap. 7 In these VPs, microvessel formation with extravasation of erythrocytes in the vasa vasorum and intimal area has been observed. 8 -10 Although new vessel formation in advanced atherosclerosis has been associated with lesion progression and instability, 10 -12 the exact molecular mechanisms that facilitate neovascularization in atherosclerosis must be further elucidated. Conclusions:Recently, we have conducted a genome-wide screen to identify new geneti...

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Section: Cheng Et Almentioning

confidence: 90%

Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions

Cheng

Tempel

Dekker

et al. 2011

Circulation Research

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“…Furthermore, in view of the potential link between HO-1 induction and plaque stabilization [75], Nrf2-mediated upregulation of HO-1 by SFN may prevent plaque destabilization/rupture in vulnerable vessels thereby offering protection from acute coronary events.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation

Shawky

Segar

2017

Pharmacological Research

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Activation of nuclear factor erythroid 2-related factor 2 (Nrf2, a transcription factor) and/or inhibition of mammalian target of rapamycin (mTOR) are implicated in the suppression of vascular smooth muscle cell (VSMC) proliferation. The present study has examined the likely regulatory effects of sulforaphane (SFN, an antioxidant) on Nrf2 activation and platelet-derived growth factor (PDGF)-induced mTOR signaling in VSMCs. Using human aortic VSMCs, nuclear extraction and siRNA-mediated downregulation studies were performed to determine the role of Nrf2 on SFN regulation of PDGF-induced proliferative signaling. Immunoprecipitation and/or immunoblot studies were carried out to determine how SFN regulates PDGF-induced mTOR/p70S6K/S6 versus ERK and Akt signaling. Immunohistochemical analysis was performed to determine SFN regulation of S6 phosphorylation in the injured mouse femoral artery. SFN (5 μM) inhibits PDGF-induced activation of mTOR without affecting mTOR association with raptor in VSMCs. While SFN inhibits PDGF-induced phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTOR), it does not affect ERK or Akt phosphorylation. In addition, SFN diminishes exaggerated phosphorylation of S6 ribosomal protein (a downstream target of p70S6K) in VSMCs in vitro and in the neointimal layer of injured artery in vivo. Although SFN promotes Nrf2 accumulation to upregulate cytoprotective genes (e.g., heme oxygenase-1 and thioredoxin-1), downregulation of endogenous Nrf2 by target-specific siRNA reveals an Nrf2-independent effect for SFN-mediated inhibition of mTOR/p70S6K/S6 signaling and suppression of VSMC proliferation. Strategies that utilize local delivery of SFN at the lesion site may limit restenosis after angioplasty by targeting mTOR/p70S6K/S6 axis in VSMCs independent of Nrf2 activation.

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“…11 The bioactive product of HO-1 CO converts via activation of soluble guanylyl cyclase, guanosine triphosphate (GTP), into cGMP. 4 Therefore, HO-1 inhibition of VSMC proliferation could be attributed to a rise in intracellular CO levels.…”

Section: Discussionmentioning

confidence: 99%

“…As previously reported, HO-1 inhibits cell cycle progression in VSMCs via a p21 cip1 -dependent pathway. 4 To distinguish between the effect of HO-1 on migration and cell proliferation, we conducted experiments in mitomycin-c-treated VSMCs in which cell cycle progression was blocked in the early prophase. HO-1-induced inhibition in VSMC migration was independent from the gene's effect on cell proliferation, as a decrease in VSMC migration was observed in the mitomycin-c-treated cultures in response to PDGFBB (Figure 2A) or VEGFA stimulation ( Figure 2B).…”

Section: Ho-1 Inhibits Directional Migration Of Vsmcs Under Pdgfbb Stmentioning

confidence: 99%

“…Heme degradation by HO-1 generates bioactive products that affect the vascular system, including iron, biliverdin, bilirubin, and carbon monoxide (CO). [1][2][3][4] In ECs, the protective function of HO-1 is well studied; HO-1 activation has been shown to be required for both tube formation and directional migration of ECs, a process that is attributed to the bioactive function of CO. 5 In cardiovascular disease, correlation studies in patients with atherosclerosis and knockout studies in murine atherosclerosis models have shown that HO-1 inhibits plaque growth. 4,[6][7][8] More importantly, HO-1 is a crucial factor for preventing destabilization of advanced atherosclerotic lesions into (rupture) vulnerable plaques by suppressing immune activation.…”

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confidence: 99%

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PDGF-Induced Migration of Vascular Smooth Muscle Cells Is Inhibited by Heme Oxygenase-1 Via VEGFR2 Upregulation and Subsequent Assembly of Inactive VEGFR2/PDGFRβ Heterodimers

Cheng

Haasdijk

Tempel

et al. 2012

ATVB

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Primary human aorta-derived VSMC (Lonza, Breda, NL) were cultured on gelatin-coated plates at 37°C/5% CO 2 in SmGM-2 medium Objective-In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration. Methods and Results-Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFR/VEGFR2 complexes. This compromised PDGFR phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration. Conclusion-These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFR complexes that attenuates effective PDGFR signaling. (Arterioscler Thromb Vasc Biol . 2012;32:1289-1298 .) PdGF-induced Migration of Vascular smooth

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Regulation of Vulnerable Plaque Development by the Heme Oxygenase/Carbon Monoxide System

Cited by 9 publications

References 81 publications

Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions

Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions

Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation

PDGF-Induced Migration of Vascular Smooth Muscle Cells Is Inhibited by Heme Oxygenase-1 Via VEGFR2 Upregulation and Subsequent Assembly of Inactive VEGFR2/PDGFRβ Heterodimers

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