Epigenetic regulation of smooth muscle cell plasticity

Liu, Renjing; Leslie, Kristen L; Martin, Kathleen A.

doi:10.1016/j.bbagrm.2014.06.004

Cited by 119 publications

(100 citation statements)

References 84 publications

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“…Studies demonstrate that epigenomic changes in tissues and cells play important roles in vascular remodeling and atherosclerosis. 10 DNA methylation is the most understood epigenetic modification. The effect of DNA methylation on gene expression can persist even if the risk factors are removed.…”

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confidence: 99%

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

Zhuang

Luan

et al. 2017

ATVB

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A therosclerosis is a chronic and multifactorial disease mediated by complex interplay between resident endothelial cells, vascular smooth muscle cells (VSMCs), and infiltrating macrophages. Environmental exposure to risk factors such as hyperlipidemia throughout the development of atherosclerosis causes vascular remodeling and in turn reduces arterial compliance. Although many drugs inhibiting vascular remodeling and metabolic disorder offer an effective therapeutic strategy for preventing atherosclerotic progression, none of these drugs are found to totally reverse atherosclerotic plaque in animal experiments.1,2 Furthermore, clinical trials have revealed that intensive lipid-lowering treatment with rosuvastatin or atorvastatin only leads to limited plaque regression (1.22% and 0.99%, respectively), 3,4 although routine statin treatments can significantly reduce >30% of the risk of major adverse cardiac events such as myocardial infarction. [5][6][7][8][9] The memory effects of atherosclerosis imply that the mechanisms for atherogenesis are partially independent of the risk factors. It seems that atherosclerosis would progress at its own pace, once the atherosclerotic plaques are formed. Epigenetic modifications refer to heritable changes in gene expression that are not coded in the DNA sequence itself. Studies demonstrate that epigenomic changes in tissues and cells play important roles in vascular remodeling and atherosclerosis.10 DNA methylation is the most understood epigenetic modification. The effect of DNA methylation on gene expression can persist even if the risk factors are removed. In eukaryotic genomes, DNA methyltransferases (DNMTs) catalyze the conversion of cytosines, predominantly in cytidine phosphate guanosine (CpG) dinucleotides, to 5-methylcytosine (5-mC), and then silence gene expression. The DNMT inhibitor 5-aza-2′-deoxycytidine (5-aza) is © 2016 American Heart Association, Inc. Objective-DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis. Approach and Results-In ApoE −/− mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE −/− mice. Using a carotid ligation model, we found that 5-aza-2′-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×10 4 versus 4.07±0.22×10 4 μm 2 ; P<0.01). Abnormal methylation status at the promoter of ten-eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2′-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the p...

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confidence: 99%

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

Zhuang

Luan

et al. 2017

ATVB

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Section: Resultsmentioning

confidence: 99%

“…The contractile phenotype of VSMCs is characterized by a low rate of cell proliferation and migration and high expression of contractile proteins such as α‐SMA, SM22 (transgelin), and smooth muscle myosin heavy chain 11 (MYH11) 24, 54, 55, 56, 57. The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57. Disruption of the balance of the VSMCs phenotypes (for example, a transition from a contractile phenotype to a synthetic phenotype) will favor VSMCs proliferation and migration, leading to development of neointimal formation and restenosis after vascular injury 24, 55, 56, 57, 58.…”

Section: Resultsmentioning

confidence: 99%

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Yao

et al. 2017

JAHA

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BackgroundDespite recent improvements in angioplasty and placement of drug‐eluting stents in treatment of atherosclerosis, restenosis and in‐stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury.Methods and Results AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/− mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet‐derived growth factor‐BB–induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs to the synthetic phenotype by countering the inhibitory effect of platelet‐derived growth factor‐BB on SRF expression and the formation of the myocardin/SRF/CArG‐box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet‐derived growth factor‐BB–induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1.Conclusions AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1‐MEK1/2‐ERK1/2‐Elk‐myocardin‐SRF/p27 signaling pathway.

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“…Recent studies suggest that VSMCs play a central role in the development and progression of atherosclerosis 3. During the development of atherosclerosis, VSMCs change from a contractile phenotype to a synthetic phenotype, migrate to the intima, increase their proliferative ability and promote the synthesis of extracellular matrix proteins 4, 5. VSMCs exhibit a contractile phenotype characterized by the expression of contractile marker such as α‐SMA and synthetic phenotype characterized by the expression of synthetic marker osteopontin (OPN) 3, 6.…”

Section: Introductionmentioning

confidence: 99%

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

Pan

Liu

Gao

et al. 2018

J Cellular Molecular Medi

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Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low‐density lipoprotein receptor‐deficient (LDLR−/−) mice and to elucidate the molecular processes underlying this effect. LDLR−/− mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α‐actin (α‐SMA) antibodies and anti‐osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α‐SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high‐fat‐fed LDLR−/− mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.

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Epigenetic regulation of smooth muscle cell plasticity

Cited by 119 publications

References 84 publications

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

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