BACKGROUND: The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ-Lin28a axis in restenosis. METHODS: Restenosis and atherosclerosis rat models of type 2 diabetes ( n   =  20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student's t -test and one-way analysis of variance were used for statistical analysis. RESULTS: C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitroC/EBPβ overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPβ knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBPβ hypomethylation. Additionally, Lin28a overexpression reduced C/EBPβ methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells. CONCLUSION Our findings suggest that the C/EBPβ-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.
Animals ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Muscle, Smooth, Vascular/metabolism* ; Rats ; DNA Methylation/physiology* ; CCAAT-Enhancer-Binding Protein-beta/genetics* ; Male ; Myocytes, Smooth Muscle/cytology* ; Rats, Sprague-Dawley ; RNA-Binding Proteins/genetics* ; Cells, Cultured ; Coronary Restenosis/metabolism*

BackgroundIt is known that there is a definite association between platelet distribution width (PDW) and poor prognosis in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, there are no data available regarding the prognostic significance of PDW for in-stent restenosis (ISR) in patients with CAD and T2DM. We aimed to determine the value of PDW on admission that predicted ISR in patients with CAD and T2DM.

MethodsBetween January 2012 and December 2013, a total of 5232 consecutive patients diagnosed with CAD and T2DM undergoing percutaneous coronary intervention were admitted. Three years of retrospective follow-up was undertaken. A total of 438 patients with second angiography operations were included. ISR was defined as ≥50% luminal stenosis of the stent or peri-stent segments. Continuous data were presented as the mean ± standard deviation or median (P, P) and were compared by one-way analysis of variance or Kruskal-Wallis H-test. Categorical variables were presented as percentages and were compared by Chi-square test or Fisher's exact test. The association between PDW and ISR was calculated by logistic regression analysis. A two-sided value of P < 0.05 was considered statistically significant. Statistical analyses were performed by SPSS version 22.0 for windows.

ResultsFifty-nine patients with ISR, accounting for 13.5% of the total, were included. ISR was significantly more frequent in patients with higher PDW quartiles compared with lower quartiles. We observed that PDW had a strong relationship with mean platelet volume (r = 0.647, 95% confidence interval [CI]: 0.535-0.750, P < 0.0001). The receiver-operating characteristic curves showed that the PDW cutoff value for predicting ISR rate was 13.65 fl with sensitivity of 59.3% and specificity of 72.4% (area under curve [AUC] = 0.701, 95% CI: 0.625-0.777, P < 0.001). Multivariate analysis showed that the risk of ISR increased approximately 30% when PDW increased one unit (odds ratio [OR]: 1.289, 95% CI: 1.110-1.498, P = 0.001). Patients with higher PDW, defined as more than 13.65 fl, had a 4-fold higher risk of ISR compared with lower PDW (OR: 4.241, 95% CI: 1.879-9.572, P = 0.001). Furthermore, when patients were divided by PDW quartiles values, PDW was able to predict ISR (Q2: OR = 0.762, 95% CI: 0.189-3.062, P = 0.762; Q3: OR = 2.782, 95% CI: 0.865-8.954, P = 0.086; and Q4: OR = 3.849, 95% CI: 1.225-12.097, P = 0.021, respectively; P for trend <0.0001).

ConclusionPDW is an independent predictor of ISR in patients with CAD and T2DM.

Adult ; Aged ; Blood Platelets ; metabolism ; Coronary Artery Disease ; metabolism ; therapy ; Coronary Restenosis ; metabolism ; therapy ; Diabetes Mellitus, Type 2 ; metabolism ; therapy ; Female ; Humans ; Male ; Mean Platelet Volume ; Middle Aged ; Percutaneous Coronary Intervention ; Retrospective Studies

OBJECTIVETo review the functional mechanism of apolipoprotein J (apoJ) in the process of atherosclerosis and the feasibility of apoJ as a therapeutic endpoint.

DATA SOURCESRelevant articles published in English from 1983 to present were selected from PubMed. The terms of "atherosclerosis, apolipoprotein J, clusterin (CLU), oxidative stress, and inflammation" were used for searching.

STUDY SELECTIONArticles studying the role of apoJ with atherosclerosis and restenosis after injury were reviewed. Articles focusing on the intrinsic determinants of atherosclerosis were selected. The exclusion criteria of articles were that the studies on immunologic vasculitis.

RESULTSApoJ, involved in numerous physiological process important for lipid transportation and vascular smooth muscle cell differentiation, including apoptotic cell death, cell-cycle regulation, cell adhesion, tissue remodeling, immune system regulation, and oxidative stress, plays a role in the development of clinical atherosclerosis. In the process of relieving atherosclerosis, apoJ can promote cholesterol and phospholipid export from macrophage-foam cells, and exhibit cytoprotective and anti-inflammatory actions by interacting with lots of known inflammatory proteins which may predict the onset of clinical cardiovascular events and may actually play a causal role in mediating atherosclerotic disease such as C-reactive protein, paraoxonase, and leptin. As known as CLU, apoJ has been identified to play central roles in the process of vascular smooth cells migration, adhesion, and proliferation, which can contribute significantly to restenosis after vascular injury.

CONCLUSIONSIntense effort and substantial progress have been made to identify the apoJ that relieves atherosclerosis and vascular restenosis after percutaneous coronary intervention. More work is needed to elucidate the exact mechanisms of and the interrelationship between the actions of apoJ and to successfully achieve regression of atherosclerosis by regarding it as a therapeutic endpoint.

Cardiovascular Diseases ; genetics ; mortality ; Clusterin ; genetics ; metabolism ; Coronary Artery Disease ; genetics ; metabolism ; Coronary Restenosis ; genetics ; metabolism ; Humans

OBJECTIVETo discuss whether asiaticosides could effectively reduce the endothelial cell damage as a biochemical modulator, so as to further inhibit the post-stenting intima-media membrane hyperplasia.

METHODHuman aortic smooth muscle cells and aortic fibroblasts were selected and divided into the blank group, the rapamycin group and the asiaticoside group and the rapamycin and asiaticoside group. The expressions of muscle cells and fibroblasts TGF-beta1, Smad7 and I-collagen gene were determined by RT-PCR. The expression quantity of I-collagen protein was assayed by ELISA. The coefficient of drug interaction (CDI) between rapamycin and asiaticoside was calculated. Additionally, 16 Chinese mini-swines were randomly divided into group A and group B. One sirolimus drug-eluting stent of the same type was implanted after the high-pressure pre-expansion of anterior descending artery balloon. After the operation, the group A was intravenously injected with normal saline 30 mL x d(-1). Whereas the group B was intravenously injected with asiaticoside 30 mg x kg(-1) x d(-1)(diluted to 30 mL). The expressions of plasma vWF of the two groups were measured at the 7th and 14th days after the operation. At the 28th day after the operation, tissues of the stented vessel segments were sliced and stained to calculate the vessel area, inner stent area, lumen area and neointima area

RESULTCompared with the control group, the combination group showed significant up-regulation in smooth muscle cells and fibroblast Smad7 gene, down-regulation in TGF-beta, and obvious inhibition of I-collagen gene expression (P < 0.01). As for smooth muscle cells, there was no difference in the expression of I-collagen between the combination group and the rapamycin group, with CDI at 0. 83. As for fibroblasts, there was a significant difference in the expression of I-collagen between the combination group and the rapamycin group (P < 0.05), with CDI at 0.77. Plasma vWF of the group B was significantly lower than that of the group A (P < 0.05) at the 7th and 14th days after the operation. At the 28th day after the operation, no difference was observed in vessel area and stent area between the two groups. However, the lumen area in the group B was significantly larger than that of the group A(P < 0.05), and the neointima area of the group B was significantly smaller than that of the group A (P < 0.05).

CONCLUSIONAs an effective biochemical modulator for rapamycin, asiaticosides could inhibit TGF-beta expression, significantly decrease the synthesis and secretion of extracellular matrix, further inhibit the post-stenting intima-media membrane hyperplasia and reduce the endothelial cell damage by effectively up-regulate the expression of Smad7 protein.

Animals ; Collagen ; genetics ; metabolism ; Coronary Restenosis ; drug therapy ; prevention & control ; surgery ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hyperplasia ; drug therapy ; genetics ; metabolism ; prevention & control ; Smad7 Protein ; genetics ; metabolism ; Stents ; adverse effects ; Swine ; Transforming Growth Factor beta1 ; genetics ; metabolism ; Triterpenes ; administration & dosage

BACKGROUNDThe role of plasma high sensitivity C-reactive protein (hs-CRP) in in-stent restenosis (ISR) remains controversial. We investigated plasma hs-CRP level at both admission and follow-up in patients with stable angina (SA) after successful coronary stenting in order to clarify the predictive value of hs-CRP for ISR.

METHODSWe summarized 303 consecutive chronic SA patients with coronary drug-eluting stent (DES) implantation. The ISR was analyzed by quantitative coronary analysis (QCA) at a mean follow-up of 8 months, and the patients were divided into two groups according to the detected ISR as ISR group (n = 48) and non-ISR group (n = 255). Plasma hs-CRP was examined at both admission and 8-month follow-up in all patients, standard medication continued throughout the investigation period.

RESULTSQCA presented that 48 patients (15.8%) suffered from ISR at follow-up. The basic clinical characteristics were similar between the two groups, while plasma hs-CRP was higher in ISR group than that in non-ISR group at both admission and follow-up, P < 0.001 respectively. Multivariate regression analysis indicated that plasma hs-CRP level at either admission or follow-up could independently predict ISR occurrence (OR = 5.581, 95%CI 2.532-12.302, P < 0.001 and OR = 6.299, 95%CI 2.722-14.577, P < 0.001, respectively).

CONCLUSIONSOur data indicate that plasma hs-CRP level may independently predict ISR at both admission and follow-up in SA patients with coronary DES implantation, which implies that a chronic, sustained systemic inflammatory response might be involved in ISR pathogenesis.

Aged ; Angina Pectoris ; therapy ; C-Reactive Protein ; metabolism ; Coronary Restenosis ; blood ; therapy ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis

OBJECTIVETo study the safety and efficacy of control-releasing arsenic trioxide (As2O3)-eluting stent on intimal smooth muscle cells (SMC) and type III collagen (CIII) in canine coronary artery post-stent model.

METHODSTwenty-four experimental canines were equally divided into 4 groups, the three tested groups were deployed by stents with different dosage of As2O3 (1.6 microg/mm2, 2.4 microg/mm2 and 3.2 microg/mm2 in low, median and high dose groups, respectively) and coated with polybutyl methacrylate/nano silica and poly-lactide-coglycolide in mild oversizing (stent/vessel ratio of 1.3:1) in left anterior descending (LAD) or circumflex coronary arteries (LCX), while the control group only by simple coated stent without As2O3. The effect was assessed 4 weeks after stent implantation in terms of vascular histomorphology, and changes of SMC and C III expressions were detected using immunohistochemical analysis.

RESULTSSubintimal hemorrhage, medial/adventitial necrosis, thrombosis and inflammatory cell infiltration were not found and integral endothelium could be seen under screening electron microscopy in all groups. Positive expression of SMC and CIII in the tested groups, especial in the high dose As2O3 group, was more weaker than that in control group. Histo-morphological analysis showed that the neo-genetic intimal area and vascular stenosis were lower, but the mean luminal diameter was larger in the three tested groups than that in the control group (P < 0.01). Comparisons of various indices between tested groups treated by different doses of As2O3 showed that the difference between high/median dose vs. low dose was significant (P < 0.01), but that between high dose vs. median dose was insignificant (P > 0.05).

CONCLUSIONControl-releasing As2O3-eluting stent shows a reliable and safe effect in preventing and treating post-stent restenosis by its dose-dependent inhibition on expressions of SMC and CIII to suppress the neo-genesis of intimal hyperplasia.

Animals ; Arsenicals ; administration & dosage ; pharmacology ; Collagen Type III ; metabolism ; Coronary Restenosis ; etiology ; prevention & control ; Coronary Vessels ; metabolism ; pathology ; Dogs ; Drug-Eluting Stents ; Female ; Implants, Experimental ; Male ; Muscle, Smooth, Vascular ; drug effects ; metabolism ; pathology ; Oxides ; administration & dosage ; pharmacology ; Tunica Intima ; drug effects ; pathology

Coronary Restenosis ; pathology ; Fibroblasts ; metabolism ; pathology ; Fibrosis

Coronary Restenosis ; metabolism ; Heart Valve Diseases ; Humans ; Osteopontin ; metabolism

OBJECTIVETo investigate the effectiveness and safety of triptolide-eluting stents implanted in porcine coronary arteries for restenosis prevention, and its effect on the expression of proliferating cell nuclear antigen (PCNA) and P27(kip1).

METHODSTen triptolide-eluting stents and 10 stainless steel stents (control) were implanted in 20 porcine coronary arteries at random. Four weeks later, angiography of the arteries was performed along with also histopathological and immunochemical examinations.

RESULTSThe in-stent minimal lumen diameter of triptolide group was significantly greater, and the neointimal area significantly smaller, than those of the control group (P<0.05). PCNA expression was significantly lower while P27(kip1) protein significantly higher in triptolide group than in the control group (P<0.05).

CONCLUSIONTriptolide-eluting stent can effectively inhibit neointimal formation to prevent restenosis in porcine coronary artery 4 weeks after implantation, probably by inhibiting P27(kip1) expression and consequently vascular smooth muscle cell proliferation.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; therapeutic use ; Coronary Restenosis ; prevention & control ; Coronary Vessels ; drug effects ; metabolism ; pathology ; Cyclin-Dependent Kinase Inhibitor p27 ; biosynthesis ; Diterpenes ; therapeutic use ; Drug-Eluting Stents ; Epoxy Compounds ; therapeutic use ; Immunohistochemistry ; Male ; Phenanthrenes ; therapeutic use ; Proliferating Cell Nuclear Antigen ; biosynthesis ; Random Allocation ; Swine ; Time Factors ; Tunica Intima ; drug effects ; metabolism ; pathology

OBJECTIVETo assess the effect of valsartan eluting-stents on restenosis and collagen deposition in neointima hyperplasia in rabbits.

METHODSValsartan eluting-stents and the carrier eluting-stents were made with patented multi-layers coating techniques. Bare stents (n = 8), carrier eluting-stents (n = 8) and valsartan eluting-stents (n = 10) were implanted into rabbit abdominal aortas, respectively. Quantitive angiography (QA) was performed before, immediately post and 3 months after stents implantations to determine the diameter of aortas. Rabbits were killed 3 months post stents implantation and the cross sections of the stented vessels were analyzed for neointimal formation: luminal area (LA), neointimal area (NIA), inner elastic lumina area (IELA), the maximal inner-membrane thickness (MIT) and percent stenosis. MASSON and picrosirius red staining were performed to observe the collagen deposition in neointima analyzed.

RESULTSThe mean aortic diameters measured by QA at different time points were similar between the groups. LA was significantly larger (5 016 269 microm(2) +/- 207,934 microm(2) vs. 4,345,548 microm(2) +/- 125,822 microm(2) and 4,302,061 microm(2) +/- 167,952 microm(2), P < 0.01 vs. valsartan stents) while NIA (441,577 microm(2) +/- 74,099 microm(2) vs. 1,119,635 microm(2) +/- 163,503 microm(2) and 1,135,636 microm(2) +/- 136,555 microm(2)) and MIT (116 microm +/- 12 microm vs. 240 microm +/- 30 microm and 192 microm +/- 21 microm) as well as percent stenosis (8% +/- 2% vs. 20% +/- 2% and 21% +/- 2%) were significantly reduced in valsartan eluting-stents group compared to bare and carrier stents groups. MASSON and picrosirius red staining revealed rich type III collagen deposition in neointima and spare type I collagen patched around stents struts in bare and carrier stents groups and collagen deposition was rarely seen in neointima and stents struts in valsartan eluting-stents group.

CONCLUSIONValsartan eluting-stents inhibited neointimal hyperplasia by decreasing collagen deposition.

Animals ; Collagen ; metabolism ; Coronary Restenosis ; metabolism ; pathology ; therapy ; Coronary Vessels ; pathology ; Drug-Eluting Stents ; Female ; Graft Occlusion, Vascular ; metabolism ; pathology ; Hyperplasia ; Male ; Rabbits ; Tetrazoles ; therapeutic use ; Tunica Intima ; pathology ; Valine ; analogs & derivatives ; therapeutic use ; Valsartan