Carotid Stent Restenosis and Thrombosis in Rabbits: The Effect of Antiplatelet Agents

2020 ◽  
Vol 25 (6) ◽  
pp. 570-577
Author(s):  
Nikolaos P. E. Kadoglou ◽  
Marianna Stasinopoulou ◽  
Triantafyllos Giannakopoulos ◽  
Anastasios Papapetrou ◽  
Constantinos Dimitriou ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Carotid Arteries ◽  
Antiplatelet Agents ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
Total Occlusion ◽  
Stent Restenosis ◽  
Vascular Walls ◽  
New Zealand White Rabbits ◽  
Group 3

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.

MicroRNA-17-5p, a novel endothelial cell modulator, controls vascular re-endothelialization and neointimal lesion formation

Vascular ◽  
2021 ◽  
pp. 170853812110676
Author(s):  
Xiaopei Liu ◽  
Jing Chen ◽  
Gen Liu ◽  
Bofang Zhang ◽  
Xing Jin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Carotid Artery ◽  
Luciferase Reporter ◽  
Cgmp Level ◽  
Vascular Remodelling ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
Software Analysis ◽  
Vascular Walls ◽  
Arterial Endothelial Cells

Background The functions of miR-17-5p in tumorigenesis have been explored. However, their functionalities in arterial endothelial cells (ECs) have not been investigated. Besides, the issue of vascular remodelling is barely addressed. Objectives The study aimed to determine the effect of overexpression or inhibition of miR-17-5p on arterial endothelial cells’ (ECs) function and vascular remodelling in vitro and the rat carotid arteries model. Methods Quantitative RT-PCR analysis was performed to examine the expression of miR-17-5p. Then, gain-of-function and loss-of-function approaches were employed to investigate the functional roles of miR-17-5p in cultured human coronary artery endothelial cells (HCAECs); further, TargetScan software analysis and luciferase reporter activity assay were performed to investigate the potential mechanism. Lastly, the results of the cell segment were verified in a rat carotid artery balloon injury model by Western blot analysis, measurement of the vascular cGMP level and plasma 8-iso-prostaglandin F2 (8-iso-PGF2) testing. Moreover, morphometric analysis was implemented to detect the re-endothelialization and neointimal formation in rat carotid artery after balloon injury. Results This study firstly found that miR-17-5p expression was upregulated in the injured vascular walls and highly expressive in ECs; overexpression of miR-17-5p inhibited HCAECs’ proliferation and migration, whereas miR-17-5p knockdown strengthened its proliferative and migratory roles, influenced inflammatory response, through regulating VEGRA and VEGFR2. It was found that miR-17-5p bind to VEGFA and VEGFR2 at the 3′UTR. Next, downregulation of miR-17-5p promotes re-endothelialization, and attenuates neointimal formation as measured by the I/M ratio (0.63±0.05 vs 1.45±0.06, antagomiR-17-5p vs. Lenti-NC, p < 0.05). In addition, the functional recovery of the endothelium was also accelerated by miR-17-5p knockdown. Conclusion Our study suggests that miR-17-5p is a feasible strategy for the selective modulation of endothelialization and vascular remodelling through regulating VEGFA and VEGFR2.

Abstract 338: p55γ Suppresses VSMC Proliferation and Neointimal Formation

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]).

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

1999 ◽  
Vol 19 (3) ◽  
pp. 727-733 ◽  
Author(s):  
Yasushi Numaguchi ◽  
Keiji Naruse ◽  
Mitsunori Harada ◽  
Hiroyuki Osanai ◽  
Shinji Mokuno ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Carotid Arteries ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
Prostacyclin Synthase

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

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.

scholarly journals Aerobic Exercise Training Inhibits Neointimal Formation via Reduction of PCSK9 and LOX-1 in Atherosclerosis

Biomedicines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 92 ◽  
Author(s):  
Wei Li ◽  
Heegeun Park ◽  
Erling Guo ◽  
Wooyeon Jo ◽  
Kyu Min Sim ◽  
...  
Keyword(s):  
Exercise Training ◽  
Aerobic Exercise ◽  
High Fat Diet ◽  
Carotid Arteries ◽  
Ldl Receptor ◽  
Aerobic Exercise Training ◽  
Proprotein Convertase ◽  
High Fat ◽  
Neointimal Formation ◽  
Common Carotid Arteries

The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat diet were randomly divided into three groups; these were the sham-operated control (SC), the balloon-induced control (BIC) and the balloon-induced exercise (BIE). The aerobic exercise training groups were performed on a treadmill. The major findings were as follows: first, body weight gain was significantly decreased by aerobic exercise training compared to the BIC without change of energy intake. Second, neointimal formation was significantly inhibited by aerobic exercise training in the balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. Third, low-density lipoprotein (LDL) receptor (LDLr) expression was significantly increased by aerobic exercise training in the livers of the high-fat diet group compared to the BIC, but not the proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Fourth, aerobic exercise training significantly decreased the expression of PCSK9, the lectin-like oxidized LDL receptor-1 (LOX-1), and vascular cell adhesion molecule-1 (VCAM-1) in balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. In conclusion, our results suggest that aerobic exercise training increases LDLr in the liver and inhibits neointimal formation via the reduction of PCSK9 and LOX-1 in balloon-induced common carotid arteries of high-fat-diet-induced rats.

N-acetyl-cysteine Reduces Neointimal Thickening and Procoagulant Activity after Balloon-induced Injury in Abdominal Aortae of New Zealand White Rabbits

2001 ◽  
Vol 85 (04) ◽  
pp. 724-729 ◽  
Author(s):  
Paul Eisenberg ◽  
Antonietta Martelli ◽  
Patrizia Orsi ◽  
Daniela Sini ◽  
Paolo Spallarossa ◽  
...  
Keyword(s):  
Procoagulant Activity ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
Neointimal Thickening ◽  
Thrombin Activity ◽  
New Zealand White Rabbits ◽  
Before And After ◽  
Acetyl Cysteine ◽  
And Oxidative Stress

Summary Background: Procoagulant activity and oxidative stress generated by balloon injury to normal vessels promote the migration of medial smooth muscle cells and their proliferation in the intima. We hypothesised that administering levo N-acetyl-cysteine (NAC) i.v. at the time of injury, and s.c. before and after injury would reduce neointimal formation 4 weeks later and would regulate procoagulant activity in vessels with neointima undergoing ballooning a second time. Methods and Results: at the time of injury rabbits received: NAC, unfractionated heparin (HEP) or both (NAC + HEP). Neointimal thickening at 28 days, calculated as the ratio between the intimal and medial area, was attenuated after NAC, HEP and NAC+HEP by 39%, 30% and 47% respectively when compared to untreated injured animals (CONTROLS) (p 0.05). At 28 days, bound thrombin activity and platelet adhesion 1 h after a repeated balloon injury decreased in animals receiving NAC, HEP and NAC+HEP by 54%, 63% and 64% for thrombin activity (p 0.05 vs CONTROLS), and by 56%, 66% and 75% respectively for 111Indium-platelet deposition (p 0.05 vs CONTROLS). Conclusions: NAC in-vivo was effective in reducing neointimal thickening and procoagulant response after balloon injury.

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

Circulation ◽  
2001 ◽  
Vol 103 (1) ◽  
pp. 133-139 ◽  
Author(s):  
Hiroyuki Morita ◽  
Hiroki Kurihara ◽  
Shigetaka Yoshida ◽  
Yuichiro Saito ◽  
Takayuki Shindo ◽  
...  
Keyword(s):  
Carotid Arteries ◽  
Neointima Formation ◽  
Balloon Injury

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

Hypertension ◽  
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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