E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression

Wu, Min; Zhou, Junlan; Cheng, Min; Boriboun, Chan; Biyashev, Dauren; Wang, Hong; Mackie, Alexander R; Thorne, Tina; Chou, Jonathan; Wu, Yiping; Chen, Zhishui; Liu, Qinghua; Yan, Hong‐Bin; Yang, Yali; Jie, Chunfa; Tang, Yaoliang; Zhao, Ting C.; Taylor, Robert N.; Kishore, Raj; Losordo, Douglas W.; Qin, Gangjian

doi:10.1093/cvr/cvu222

Cited by 31 publications

(43 citation statements)

References 44 publications

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“…In cardiac fibroblasts subjected to hypoxia, the overexpression of E2F1 increased the expression of TP53, which was required to repress the expression VEGF-A; while a decrease in PIGF occurred independently of the TP53 status of these cells. These results suggested that E2F1 promotes the expression of pro-angiogenic factors through both TP53-dependent and TP53 independent mechanisms (Wu et al, 2014). Conversely to previous observations made in tumor cells, MDM2-deficiency in cardiac cells was reported to enhance E2F1 transcriptional activity and to have detrimental effects on the heart homeostasis (Hauck et al, 2017) (see below Part 'Insight from MDM2 transgenic mice').…”

Section: Mdm2 E2f1 and The Ischemic Heartmentioning

confidence: 82%

“…Interestingly, E2F1-deficient mice show improved cardiac function, reduced size of myocardial infarction, and enhanced post-infarction cardiac angiogenesis after ligation of the left anterior descending coronary artery. These beneficial effects of E2F1 deficiency in the ischemic heart were due to an upregulation of pro-angiogenic factors (i.e., vascular endothelial growth factor A, VEGF-A and placental growth factor, PIGF (Wu et al, 2014). In cardiac fibroblasts subjected to hypoxia, the overexpression of E2F1 increased the expression of TP53, which was required to repress the expression VEGF-A; while a decrease in PIGF occurred independently of the TP53 status of these cells.…”

Section: Mdm2 E2f1 and The Ischemic Heartmentioning

confidence: 99%

“…E2F1 stabilizes TP53 and represses the expression of VEGF-R2, facilitating apoptosis in endothelial cells and inhibition of angiogenesis after MI (Wu et al, 2014) FoxO1, Forkhead box protein O1…”

Section: Growth Factor Responsive Kinasesmentioning

confidence: 99%

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Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

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Section: Mdm2 E2f1 and The Ischemic Heartmentioning

confidence: 82%

Section: Mdm2 E2f1 and The Ischemic Heartmentioning

confidence: 99%

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Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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“…53 In the SU5416 group, animals were treated with a SU5416 intraperitoneal injection (Selleck Chemical, 25 mg/kg, every 3 days) from 1 day after Lenti-HRE-MMP-9 brain injection. 54 The vehicle SB-3CT and SU5416 were dissolved in 10% DMSO normal saline solution. The control groups also received the same amount of 10% DMSO NS solution injections.…”

Section: Experimental Designmentioning

confidence: 99%

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Cai

Jiang

et al. 2017

Molecular Therapy

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Matrix metalloproteinase 9 (MMP-9) plays a beneficial role in the delayed phase of middle cerebral artery occlusion (MCAO). However, the mechanism is obscure. Here, we constructed hypoxia response element (HRE)-regulated MMP-9 to explore its effect on glial scars and neurogenesis in delayed ischemic stroke. Adult male Institute of Cancer Research (ICR) mice underwent MCAO and received a stereotactic injection of lentivirus carrying HRE-MMP-9 or normal saline (NS)/lentivirus-GFP 7 days after ischemia. We found that HRE-MMP-9 improved neurological outcomes, reduced ischemia-induced brain atrophy, and degraded glial scars (p < 0.05). Furthermore, HRE-MMP-9 increased the number of microvessels in the peri-infarct area (p < 0.001), which may have been due to the accumulation of endogenous endothelial progenitor cells (EPCs) in the peri-infarct area after glial scar degradation. Finally, HRE-MMP-9 increased the number of bromodeoxyuridine-positive (BrdU)/NeuN cells and the expression of PSD-95 in the peri-infarct area (p < 0.01). These changes could be blocked by vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor SU5416 and MMP-9 inhibitor 2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane (SB-3CT). Our results provided a novel mechanism by which glial scar degradation and vascular endothelial growth factor (VEGF)/VEGFR2-dependent angiogenesis may be key procedures for neurological recovery in delayed ischemic stroke after HRE-MMP-9 treatment. Therefore, HRE-MMP-9 overexpression in the delayed ischemic brain is a promising approach for neurological recovery.

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“…In fact, a pronounced reduction of VEGF production by SLMP53-1 was observed in p53-expressing cancer cells. Indeed, it was reported that p53 indirectly suppresses VEGF expression by repressing transcription factors like SP1 [39] and E2F [40,41]. Interestingly, SLMP53-1 also inhibited the VEGF expression levels in endothelial cells, an effect associated with reduction in cell tube formation.…”

Section: Discussionmentioning

confidence: 98%

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

Ramos

Calheiros

Almeida

et al. 2020

IJMS

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The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.

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E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression

Abstract: E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF up-regulation through p53-dependent and -independent mechanisms, respectively.

Cited by 31 publications

References 44 publications

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

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