Inhibition of PTEN expression and activity by angiotensin II induces proliferation and migration of vascular smooth muscle cells

Xue, Dong; Yu, Lu‐Gang; Sun, Rong; Cheng, Ye; Cao, Hua; Yang, Keli; Dong, Yining; Wu, Yan; Guo, Xia

doi:10.1002/jcb.24315

Cited by 40 publications

(24 citation statements)

References 24 publications

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“…Angiotensin II is a strong stimulator for proliferation and migration of VSMCs and participates in the process of atherosclerosis and vascular stenosis. [26][27][28] In agreement with those studies, our results show that angiotensin II increases the proliferation and migration of VSMCs. Meanwhile, 100 µM naringenin can inhibit angiotensin II-induced proliferation, and migration.…”

Section: Discussionsupporting

confidence: 93%

Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

Chen

Zhang

et al. 2013

Biological & Pharmaceutical Bulletin

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Proliferation and migration of vascular smooth muscle cells (VSMCs) play pivotal roles in the development of restenosis after angioplasty and oxidative stress involves both processes. Naringenin, a flavanone compound found in citrus fruits, has been widely evaluated for antioxidant activity. This study was designed to explore whether naringenin could inhibit angiotensin II-induced VSMCs proliferation and migration and decrease neointimal hyperplasia in balloon injured rat carotid arteries. VSMCs were treated with or without naringenin before stimulation with 1 µM angiotensin II and twenty-four rats were subjected to carotid arteries injury and the carotid arteries were harvested at 14 d after balloon injury. The results showed naringenin led to a significant inhibition of angiotensin II-induced VSMCs proliferation and migration. Naringenin significantly attenuated the reactive oxygen species production, increased the superoxide dismutase activity and decreased the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reduced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) and the nuclear translocation of nuclear factor (NF)-κB p65 in angiotensin II-treated VSMCs. Moreover, naringenin decreased the ratio of neointima to media by 63.8% in balloon injured rat carotid arteries, and the serum level of 8-iso-prostaglandin F2α in naringenin-treated rats was significantly decreased. These results indicated naringenin exhibited antioxidant activity on angiotensin II-treated VSMCs and balloon injured rat carotid arteries and could be a potential protective agent for restenosis after angioplasty.Key words naringenin; vascular smooth muscle cell; oxidative stress; neointimal hyperplasia; angiotensin II Coronary heart disease (CHD) remains the leading cause of mortality in most developed countries and many developing countries.1,2) Percutaneous coronary intervention with or without intracoronary stent placement is widely used for treatment of symptomatic CHD and has greatly improved the survival rate.3,4) However, restenosis after angioplasty, which happen in 5-10% patients, is still a major clinical problem. 5,6) Studies have shown that abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play pivotal roles in the development of restenosis after angioplasty, as well as in atherosclerosis.7-9) Inhibition of proliferation and migration of VSMCs could remarkably attenuate the neointimal hyperplasia in animal studies. 10-12)Naringenin, a flavanone compound found in citrus fruits, such as oranges and grapes, 13) has been pharmacologically evaluated for antioxidant activity.14,15) Although some studies showed that naringenin could inhibit VSMCs proliferation and migration in vitro, 16,17) the effect and mechanism of naringenin on vascular injury are still far from clear. In this investigation, we attempted to evaluate whether naringenin could inhibit angiotensin II-induced VSMCs proliferation and migration in vitro a...

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Section: Discussionsupporting

confidence: 93%

Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

Chen

Zhang

et al. 2013

Biological & Pharmaceutical Bulletin

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“…It has been demonstrated that environmental factors, such as PDGF, endothelin, transforming growth factor, and inflammatory mediators, can induce synthetic smooth muscle cell phenotypic differentiation (24). AngII is a well-documented activator of VSMC proliferation and migration, which promotes atherosclerosis and vessel stenosis (25)(26)(27). Here, we showed that resveratrol inhibited AngII-induced proliferation and migration in A7r5 cells.…”

Section: Discussionmentioning

confidence: 58%

Resveratrol inhibits angiotensin II‑induced proliferation of A7r5 cells and decreases neointimal hyperplasia by inhibiting the CaMKII‑HDAC4 signaling pathway

et al. 2018

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Resveratrol has been reported to inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia following arterial injury; however, the underlying mechanisms remain unclear. The present study was designed to investigate the effects of resveratrol on angiotensin II (AngII)‑induced proliferation of A7r5 cells and explore the molecular mechanisms responsible for the observed effects. Resveratrol inhibited cell proliferation and migration, and decreased the AngII‑induced protein expression of α‑smooth muscle actin (α‑SMA), proliferating cell nuclear antigen (PCNA) and cyclin‑dependent kinase 4 (CDK4). Resveratrol inhibited AngII‑induced activation of intracellular Ca2+/calmodulin‑dependent protein kinase II (CaMKII) and histone deacetylases 4 (HDAC4), as well as blocking AngII‑induced cell cycle progression from the G0/G1 to S‑phase. In vivo, 4‑weeks of resveratrol treatment decreased the neointima area and the neointima/media area ratio in rats following carotid balloon injury. Resveratrol also inhibited the protein expression of total and phosphorylated CaMKII and HDAC4 in the injured arteries. In conclusion, the present study demonstrated that resveratrol attenuated AngII‑induced cell proliferation and neointimal hyperplasia by inhibiting the CaMKII‑HDAC4 signaling pathway. These findings suggest that resveratrol may potentially prevent arterial restenosis.

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“…This may be relevant since we previously demonstrated that early trauma-induced SMC apoptosis results in increased late neointima formation [10]. At later time points, apoptosis seems to be confined to SMC of the developing neointima and, therefore, may be beneficial by limiting lesion growth [30], [31], [32]. However, PTEN-activation by therapeutic means should not follow instantly after vascular dilatation but should be applied at later time points to prevent initial exacerbation of apoptosis-induced vessel injury.…”

Section: Discussionmentioning

confidence: 99%

Role of the Phosphatase PTEN in Early Vascular Remodeling

Sedding¹,

Widmer-Teske²,

Mueller³

et al. 2013

PLoS ONE

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BackgroundThe phosphatase PTEN represents an important physiological inhibitor of phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) signalling, however, the functional role of PTEN in the initial phase of angioplasty-induced vascular injury remains elusive. In the present study we sought to determine PTEN's effect on vascular smooth muscle cell (VSMC) apoptosis following acute injury in vivo and in vitro.Methods and ResultsImmunohistochemistry indicated a faint basal expression and equal distribution of PTEN in uninjured rat carotid arteries. 12 h following balloon-injury, PTEN expression was strongly increased in apoptotic (TUNEL+) VSMC. In vitro, stimulation with serum or different growth factors or subjecting VSMC to cyclic stretch had no effect on PTEN expression, whereas stimulation with H2O2 robustly increased PTEN expression in a time- and dose-dependent manner. To evaluate the functional role of PTEN expression, human VSMC were transduced with WT-PTEN. Overexpression of PTEN increased the number of apoptotic VSMC (19.8%±4.4 vs. 5.6%±2.3; P<0.001) as determined by TUNEL assay. In contrast, siRNA-mediated knock-down of PTEN attenuated the basal as well as H2O2-induced apoptosis of VSMC. Mechanistically, overexpression of PTEN prevented serum-induced Akt-phosphorylation, whereas siRNA-mediated knock down of PTEN augmented Akt-activation. Moreover, co-transfection of PTEN and a constitutive active Akt mutant prevented PTEN-dependent augmentation of VSMC apoptosis, indicating, that PTEN regulates VSMC apoptosis by inhibition of Akt phosphorylation/activation.ConclusionBy interfering with the PI3-K/Akt-dependent survival signalling, the oxidative stress-induced up regulation of PTEN in VSMC of injured arteries augments the sensitivity of VSMC to apoptotic stimuli in the early phase following vascular injury, augmenting the initial injury and cell loss of the injured vessel wall. Thus, these data add to our understanding of PTEN's role during vascular remodelling.

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Inhibition of PTEN expression and activity by angiotensin II induces proliferation and migration of vascular smooth muscle cells

Cited by 40 publications

References 24 publications

Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

Resveratrol inhibits angiotensin II‑induced proliferation of A7r5 cells and decreases neointimal hyperplasia by inhibiting the CaMKII‑HDAC4 signaling pathway

Role of the Phosphatase PTEN in Early Vascular Remodeling

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