The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury

Background: The purpose of the study was the comparative assessment of ticagrelor and clopidogrel effects on carotid post-balloon injury (PBI) and on post carotid artery stenting (CAS) rate of in-stent restenosis (ISR) and in-stent thrombosis in atherosclerotic rabbits. Methods: Forty-eight New Zealand white rabbits on high-fat diet were randomized into 4 groups: A1: PBI and clopidogrel (30 mg/kg/d), A2: PBI and ticagrelor (21 mg/kg twice daily), B1: PBI, CAS, and clopidogrel (30 mg/kg/d), B2: PBI, CAS, and ticagrelor (21 mg/kg twice daily). All rabbits received orally aspirin (10 mg/kg/d) and interventions were performed in their right carotid arteries (RCAs). Optical coherence tomography (OCT) and carotid angiography were performed at end point, while platelet aggregation and lipid profile were measured. After euthanasia both carotids were obtained for histological examination. Results: In B1 group, 3 rabbits presented thrombotic total occlusion of the stents, while none such episode was observed in B2 group. The neointimal areas in RCAs, calculated by OCT, did not differ between A1 and A2 groups, and between B1 and B2 groups ( P > .05). From the histological findings, the intima/(media + intima) percentage (%) in RCAs of balloon-injured rabbits did not present any difference between groups ( P = .812). Similarly, the immunohistochemically determined accumulation of endothelial cells and macrophages on vascular walls was equivalent between groups ( P > .05). Conclusion: Following carotid balloon injury and stenting, clopidogrel and ticagrelor did not show any differential effects on the extent of neointimal formation and ISR in atherosclerotic rabbits receiving aspirin. Three thrombotic stent occlusions were noted in the clopidogrel treatment group, but this finding was not statistically significant.

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Molecular Mechanism of (−)-Epigallocatechin-3-gallate on Balloon Injury-Induced Neointimal Formation and Leptin Expression

Journal of Agricultural and Food Chemistry ◽

10.1021/jf404479x ◽

2014 ◽

Vol 62 (6) ◽

pp. 1213-1220 ◽

Cited By ~ 7

Author(s):

Chiu-Mei Lin ◽

Sheng-Wen Hou ◽

Bao-Wei Wang ◽

Jiann-Ruey Ong ◽

Hang Chang ◽

...

Keyword(s):

Molecular Mechanism ◽

Balloon Injury ◽

Neointimal Formation ◽

Leptin Expression

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Molecular mechanism of green microalgae, Dunaliella salina, involved in attenuating balloon injury-induced neointimal formation

British Journal Of Nutrition ◽

10.1017/s0007114510000693 ◽

2010 ◽

Vol 104 (3) ◽

pp. 326-335 ◽

Cited By ~ 4

Author(s):

Ming-Jyh Sheu ◽

Hsu-Chen Cheng ◽

Yi-Chung Chien ◽

Pei-Yu Chou ◽

Guang-Jhong Huang ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Molecular Mechanism ◽

Dunaliella Salina ◽

Flow Cytometric Analysis ◽

Nuclear Antigen ◽

Brdu Incorporation ◽

Dependent Manner ◽

Balloon Injury ◽

Neointimal Formation

The pathological mechanism of restenosis is primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMC). The preventive effects of ethanol extract of Dunaliella salina (EDS) on balloon injury-induced neointimal formation were investigated. To explore its molecular mechanism in regulating cell proliferation, we first showed that EDS markedly reduced the human aortic smooth muscle cell proliferation via the inhibition of 5′-bromo-2′-deoxyuridine (BrdU) incorporation at 40 and 80 μg/ml. This was further supported by the G0/G1-phase arrest using a flow cytometric analysis. In an in vivo study, EDS at 40 and 80 μg/ml was previously administered to the Sprague–Dawley rats and found that the thickness of neointima, and the ratio of neointima:media were also reduced. EDS inhibited VSMC proliferation in a dose-dependent manner following stimulation of VSMC cultures with 15 % fetal bovine serum (FBS). Suppressed by EDS were 15 % FBS-stimulated intracellular Raf, phosphorylated extracellular signal-regulated kinases (p-Erk) involved in cell-cycle arrest and proliferating cell nuclear antigen. Phosphorylated focal adhesion kinase (p-FAK) was also suppressed by EDS. Also active caspase-9, caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) protein expression levels were increased by administration with EDS; the apoptotic pathway may play an important role in the regulatory effects of EDS on cell growth. These observations provide a mechanism of EDS in attenuating cell proliferation, thus as a potential intervention for restenosis.

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Abstract 338: p55γ Suppresses VSMC Proliferation and Neointimal Formation

Circulation Research ◽

10.1161/res.115.suppl_1.338 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Chun-Mei Cao ◽

Ning Xie ◽

Yuan Yao ◽

Yan Zhang ◽

Rui-Ping Xiao

Keyword(s):

Carotid Arteries ◽

P53 Protein ◽

Vascular Diseases ◽

Regulatory Subunit ◽

Quiescent State ◽

Balloon Injury ◽

Neointimal Formation ◽

Adenoviral Gene Transfer ◽

Vsmc Proliferation

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to various vascular diseases, but the factors that maintain VSMCs in a quiescent state remain poor understood. Phosphatidylinositol 3 kinases (PI3Ks) are important protein kinases that regulate vascular cell proliferation, but the biological and pathological functions of p55γ, a regulatory subunit of PI3K, and its regulation in the cardiovascular system are completely unknown. We aimed to determine the relationship between p55γ and vascular proliferation and neointimal formation. In the present study, we have demonstrated that p55γ expression is markedly downregulated in primary cultured VSMCs in response to mitogenic stimulation and in carotid arteries after balloon injury, and that overexpression p55γ profoundly inhibits mitogenic stimuli and injury induced VSMC proliferation as well as neointimal formation. p55γ overexpression inhibited, whereas knockdown of p55γ promoted PDGF-BB- and serum-induced VSMC proliferation. Importantly, in vivo adenoviral gene transfer of p55γ into carotid arteries attenuated, while knockdown of p55γenhanced balloon injury-induced neointimal formation. Furthermore, p55γ sequentially upregulated p53 and p21, resulting in cell-cycle arrest in S phase; knockdown of either p53 or p21 blocked p55γ-induced VSMC growth arrest. Mechanistically, p55γ interacted with and stabilized p53 protein by blocking MDM2-mediated p53 ubiquitination and degradation, subsequently activating its target gene p21. Concurrently, p55γ upregulated Bcl-xl expression, which counterbalanced p53-mediated apoptosis. These findings mark p55γ as a novel upstream regulator of the p53-p21 signaling pathway which negatively regulates VSMC proliferation, suggesting that malfunction of p55γ may trigger vascular proliferative disorders. * Correspondence to Chun-Mei Cao ([email protected]) or Rui-Ping Xiao ([email protected]).

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Prostacyclin Synthase Gene Transfer Accelerates Reendothelialization and Inhibits Neointimal Formation in Rat Carotid Arteries After Balloon Injury

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.19.3.727 ◽

1999 ◽

Vol 19 (3) ◽

pp. 727-733 ◽

Cited By ~ 47

Author(s):

Yasushi Numaguchi ◽

Keiji Naruse ◽

Mitsunori Harada ◽

Hiroyuki Osanai ◽

Shinji Mokuno ◽

...

Keyword(s):

Gene Transfer ◽

Carotid Arteries ◽

Balloon Injury ◽

Neointimal Formation ◽

Prostacyclin Synthase

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13‐MTD prevents neointimal formation in rat carotid arteries after balloon injury

The FASEB Journal ◽

10.1096/fasebj.21.5.a518 ◽

2007 ◽

Vol 21 (5) ◽

Author(s):

Chieh‐Hsi Wu ◽

Ming‐Jyh Sheu

Keyword(s):

Carotid Arteries ◽

Balloon Injury ◽

Neointimal Formation

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Dihydroartemisinin ameliorates balloon injury-induced neointimal formation through suppressing autophagy in vascular smooth muscle cells

Biological Chemistry ◽

10.1515/hsz-2020-0233 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Xiaoyuan Wang ◽

Junpeng Wu ◽

Haiyang Zhang ◽

Bei Sun ◽

Renping Huang

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Carotid Arteries ◽

Muscle Cells ◽

Therapeutic Effects ◽

Balloon Injury ◽

Neointimal Formation ◽

Phenotypic Transition

Abstract The present study was designed to investigate the therapeutic effects of injection of dihydroartemisinin (DHA) into the balloon-injured carotid arteries on balloon injury-induced neointimal formation and to explore whether autophagy is involved in the action of DHA. Percutaneous transluminal balloon angioplasty was performed in Sprague-Dawley rats to induce neointimal formation, immediately after which DHA (100 μmol/l×1 ml) and/or Rapamycin (1 mg/100 μl), were injected into the balloon-injured carotid arteries. After 14 d, the serum samples and carotid artery tissues were harvested for analysis. Rat aortic vascular smooth muscle cells (VSMCs) were pretreated with DMSO (vehicle), DHA (1, 10, and 100 μmol/l), or 3-methyladenine (3-MA; 10 mM) for 1 h and then stimulated with plateletderived growth factor-BB (PDGF-BB; 10 ng/ml) for another 24 h. Animal experiments showed that DHA attenuated the balloon injury-induced neointimal formation, inflammation and VSMC phenotypic transition by inhibiting the balloon injury-induced autophagy activation. In vitro results showed that DHA attenuated the PDGF-BB-induced VSMC phenotypic transition, proliferation, and migration by inhibiting the PDGF-BB-induced autophagy activation. Taken together, DHA ameliorates balloon injury-induced neointimal formation through suppressing autophagy. This study provides insights into the development of a drug-eluting stent using DHA.

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Molecular mechanism of green microalgae, Dunaliella salina, involved in attenuating balloon injury-induced neointimal formation – RETRACTION

British Journal Of Nutrition ◽

10.1017/s0007114513001372 ◽

2013 ◽

Vol 109 (11) ◽

pp. 2113-2113

Author(s):

Ming-Jyh Sheu ◽

Hsu-Chen Cheng ◽

Yi-Chung Chien ◽

Pei-Yu Chou ◽

Guang-Jhong Huang ◽

...

Keyword(s):

Molecular Mechanism ◽

Dunaliella Salina ◽

Green Microalgae ◽

Balloon Injury ◽

Neointimal Formation

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Diet-Induced Hyperhomocysteinemia Exacerbates Neointima Formation in Rat Carotid Arteries After Balloon Injury

Circulation ◽

10.1161/01.cir.103.1.133 ◽

2001 ◽

Vol 103 (1) ◽

pp. 133-139 ◽

Cited By ~ 66

Author(s):

Hiroyuki Morita ◽

Hiroki Kurihara ◽

Shigetaka Yoshida ◽

Yuichiro Saito ◽

Takayuki Shindo ◽

...

Keyword(s):

Carotid Arteries ◽

Neointima Formation ◽

Balloon Injury

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Abstract P259: Endothelial Acid Sphingomyelinase Gene Determines Inflammasome Activation and Atherosclerotic Lesions in Carotid Arteries During Hypercholesterolemia

Hypertension ◽

10.1161/hyp.66.suppl_1.p259 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Min Xia ◽

Krishna M Bioni ◽

Yang Chen ◽

Xiang Li ◽

Ashley L Pitzer ◽

...

Keyword(s):

Carotid Arteries ◽

Acid Sphingomyelinase ◽

Receptor Protein ◽

Inflammasome Activation ◽

Neointimal Formation ◽

Atherosclerotic Lesions ◽

Junction Protein ◽

Nlrp3 Inflammasomes

Nucleotide oligomerization domain (NOD)-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasome has been reported to be activated by atherogenic factors, thereby triggering endothelial injury and consequent atherosclerotic lesions in the arterial wall. However, the mechanism activating and regulating Nlrp3 inflammasomes remains poorly understood. The present study tested whether membrane raft (MR) signaling platforms associated with acid sphingomyelinase (ASM) and its product ceramide (Ce) importantly contribute to the activation of Nlrp3 inflammasomes and atherosclerotic lesions during hypercholesterolemia (HC). By confocal microscopy and biochemical analyses, we demonstrated the formation and activation of Nlrp3 inflammasomes in the intima of the carotid arteries of Asm +/+ mice with HC (as shown by a 2-fold increase in caspase-1 activity and a 6-fold enhancement of IL-1β positive stain areas), but not in Asm -/- mice. In endothelium-specific ASM transgenic mice (EC-Asm trg ), this inflammasome formation and activation were enhanced. Correspondingly, HC-induced increases in IL-1β production, ASM expression, Ce level and MR-gp91 phox clustering in the carotid intima were abolished in Asm -/- mice, but enhanced in EC-Asm trg mice. Functionally, endothelium-dependent vasodilation (EDVD) in carotid arteries in vivo (by ultrasound flowmetry) and in vitro (in perfused artery) was impaired by HC in Asm +/+ mice by 33% and 54%, respectively. This endothelial dysfunction was not observed in Asm -/- mice. The endothelial tight junction protein, ZO-1 was reduced by HC in both Asm +/+ and EC-Asm trg mice, but not in Asm -/- mice. It was also found that HC-increased neointimal formation, T-cell infiltration, and fibrosis in 2-week partially ligated carotid arteries (PLCA) occurred in Asm +/+ mice, but not in Asm -/- mice with HC. EC-Asm trg mice even exhibited more severe inflammatory and atherosclerotic lesions. All these results suggest that Asm gene and related MR clustering are essential to endothelial inflammasome activation and dysfunction in carotid arteries, ultimately determining the extent of atherosclerotic lesions.

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