Association between plasma BMP-2 and in-stent restenosis in patients with coronary artery disease.

OBJECTIVE: This study aimed to assess the association between plasma bone morphogenetic protein-2 (BMP-2) level and in-stent restenosis in patients with coronary artery disease. METHODS: A total of 96 patients who underwent percutaneous coronary intervention (PCI) and were followed up after PCI were enrolled in this study. 47 patients diagnosed with in-stent restenosis (ISR) were recruited to ISR group and 49 patients without ISR were recruited to Control group according to the results of coronary angiography (CAG). Baseline characteristic data were collected, and plasma BMP-2 level was evaluated. The results were analyzed using logistic regression. RESULTS: There were 47 patients in the ISR group and 49 patients in the Control group. Plasma levels of BMP-2 were higher in the ISR group than in the non-ISR group [20.96 (18.44, 27.05) pg/ml vs. 29.53 (25.03, 34.07) pg/ml, P<0.01]. Furthermore, the ISR group had significantly longer stent lengths and lower stent diameters than the Control group (P<0.01 and P<0.01, respectively). In multivariate analysis, BMP-2 level, diabetes, stent length and stent diameter were independently associated with ISR [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18, P<0.01; OR=4.75, 95% CI=(1.44-15.61), P=0.01; OR=1.06, 95% CI=(1.02-1.11), P<0.01; and OR=0.15, 95% CI=(0.02-0.95), P=0.04, respectively]. CONCLUSIONS: Increased BMP-2 levels were independently associated with ISR in patients with coronary artery disease. Plasma BMP-2 may be useful in predicting ISR.

Impact of Chronic Obstructive Pulmonary Disease on Long-Term Outcome in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

Objective. The aim of this study was to investigate the association between COPD and major adverse cardiovascular and cerebral events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). Methods. 2,362 patients who underwent PCI were included in this study. Subjects were divided into 2 groups: with COPD (n = 233) and without COPD (n = 2,129). Cox proportional hazards models were analyzed to determine the effect of COPD on the incidence of MACCE. Results. The patients with COPD were older (P < 0.0001) and were more likely to be current smokers (P = 0.02) and have had hypertension (P = 0.02) and diabetes mellitus (P = 0.01). Prevalence of serious cardiovascular comorbidity was higher in the patients with COPD, including a history of MI (P = 0.02) and HF (P < 0.0001). Compared with non-COPD group, the COPD group showed a higher risk of all-cause death (hazard ratio (HR): 2.45, P < 0.0001), cardiac death (HR: 2.53, P = 0.0002), MI (HR: 1.387, P = 0.027), and HF (HR: 2.25, P < 0.0001). Conclusions. Patients with CAD and concomitant COPD are associated with a higher incidence of MACCE (all-cause death, cardiac death, MI, and HF) compared to patients without COPD. The patients with a history of COPD have higher in-hospital and long-term mortality rates than those without COPD after PCI.

Plasma Levels of microRNA-145 Are Associated with Severity of Coronary Artery Disease.

BACKGROUND AND OBJECTIVE: MicroRNAs (miRNAs) have been shown to be associated with various physiological and pathological conditions, including inflammation and cardiovascular disease, but little is known about their relationship with the presence of coronary artery disease (CAD) and disease severity. METHODS: A total of 195 consecutive subjects who underwent coronary angiography for chest pain evaluation were enrolled in this study. In CAD patients severity of coronary lesions was assessed by the number of diseased vessels and the Synergy between PCI with Taxus and Cardiac surgery score (SYNTAX score). Plasma levels of miRNA-145 were quantified by real-time quantitative polymerase chain reaction test, and logarithmic transformation of miRNA-145 levels (Ln_miRNA-145) was used for analyses due to its skewed distribution. RESULTS: Of the 195 total subjects 167 patients were diagnosed as having CAD. Ln_miRNA-145 was significantly lower in CAD patients compared with the non-CAD group (-6.11 ± 0.92 vs. -5.06 ± 1.25; p < 0.001). In multivariable linear regression analyses CAD was significantly associated with lower Ln_miRNA-145 (Estimate, -0.50; standard error (SE), 0.11; p < 0.0001). Furthermore, among CAD patients, three-vessel disease, higher SYNTAX scores and STEMI were significantly associated with lower Ln_miRNA-145 ([Estimate, -0.40; SE, 0.07; p < 0.0001]; [Estimate, -0.02, SE, 0.10; p = 0.005] and [Estimate, -0.35, SE, 0.10; p < 0.001] respectively). CONCLUSIONS: Lower plasma levels of miRNA-145 were significantly associated with the presence as well as severity of CAD. As a potential biomarker for CAD, plasma miRNA-145 may be useful in predicting CAD and its severity in patients presenting with chest pain.

Increased plasma BMP-2 levels are associated with atherosclerosis burden and coronary calcification in type 2 diabetic patients.

BACKGROUND: Although Bone morphogenetic protein-2 (BMP-2) is a known mediator of bone regeneration and vascular calcification, to date no study has investigated the relationship between BMP-2 and type 2 diabetes mellitus (T2DM) and its possible role in coronary artery disease (CAD). The purpose of this study is to evaluate the relationship of BMP-2 with atherosclerosis and calcification in patients with T2DM. METHODS: 124 subjects were enrolled in this study: 29 patients with T2DM and CAD; 26 patients with T2DM and without CAD; 36 patients with CAD and without T2DMand 34 without T2DM or CAD (control group). Severity of coronary lesions was assessed using coronary angiography and intravascular ultrasound (IVUS). Plasma BMP-2 levels were quantified using a commercially available ELISA kit. RESULTS: Compared to the control group, the mean plasma BMP-2 level was significantly higher in T2DM patients with or without CAD (20.1 ± 1.7 or 19.3 ± 1.5 pg/ml, vs 17.2 ± 3.3 pg/ml, P < 0.001). In a multivariable linear regression analysis, both T2DM and CAD were significantly and positively associated with BMP-2 (Estimate, 0.249; standard error (SE), 0.063; p <0.0001; Estimate, 0.400; SE, 0.06; p < 0.0001). Plasma BMP-2 was also strongly correlated with glycosylated hemoglobin A1c (HbA1c) (Spearman ρ = -0.31; p = 0.0005). SYNTAX score was also significantly associated with BMP-2 (Spearman ρ = 0.46; p = 0.0002). Using the results from IVUS, plasma BMP-2 levels were shown to positively correlate with plaque burden (Spearman ρ = 0.38, P = 0.002) and plaque calcification (Spearman ρ =0.44, P = 0.0003) and to negatively correlate with lumen volume (Spearman ρ =0.31, P = 0.01). CONCLUSIONS: Our study demonstrates that patients with T2DM had higher circulating levels of BMP-2 than normal controls. Plasma BMP-2 levels correlated positively with plaque burden and calcification in patients with T2DM.

BMP-2 overexpression augments vascular smooth muscle cell motility by upregulating myosin Va via Erk signaling.

BACKGROUND: The disruption of physiologic vascular smooth muscle cell (VSMC) migration initiates atherosclerosis development. The biochemical mechanisms leading to dysfunctional VSMC motility remain unknown. Recently, cytokine BMP-2 has been implicated in various vascular physiologic and pathologic processes. However, whether BMP-2 has any effect upon VSMC motility, or by what manner, has never been investigated. METHODS: VSMCs were adenovirally transfected to genetically overexpress BMP-2. VSMC motility was detected by modified Boyden chamber assay, confocal time-lapse video assay, and a colony wounding assay. Gene chip array and RT-PCR were employed to identify genes potentially regulated by BMP-2. Western blot and real-time PCR detected the expression of myosin Va and the phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Immunofluorescence analysis revealed myosin Va expression locale. Intracellular Ca(2+) oscillations were recorded. RESULTS: VSMC migration was augmented in VSMCs overexpressing BMP-2 in a dose-dependent manner. siRNA-mediated knockdown of myosin Va inhibited VSMC motility. Both myosin Va mRNA and protein expression significantly increased after BMP-2 administration and were inhibited by Erk1/2 inhibitor U0126. BMP-2 induced Ca(2+) oscillations, generated largely by a "cytosolic oscillator". CONCLUSION: BMP-2 significantly increased VSMCs migration and myosin Va expression, via the Erk signaling pathway and intracellular Ca(2+) oscillations. We provide additional insight into the pathophysiology of atherosclerosis, and inhibition of BMP-2-induced myosin Va expression may represent a potential therapeutic strategy.

[Effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention in coronary artery disease patients with diabetes mellitus].

OBJECTIVE: To explore the effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients with diabetes mellitus (DM). METHODS: A total of 120 CAD patients with DM undergoing PCI were randomly assigned to receive conventional (control, n = 60) and additional allitridi treatment (120 mg/day, n = 60) for 3 months.Serum nitric oxide (NO) and intercellular adhesion molecule 1 (ICAM-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) immediately and at 3 months post-PCI. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD). Duration of follow-up was 1 year after PCI. RESULTS: The clinical characteristics, serum NO and ICAM-1 levels and FMD at baseline were not different between two groups. At Month 3 post-PCI, serum NO level was markedly higher ((147 ± 32) vs (112 ± 24) µmol/L, P = 0.009) and serum ICAM-1 level was significantly lower ((182 ± 21) vs (232 ± 29) µmol/L, P = 0.021) in the allitridi group than in the control group.Furthermore, treatment of allitridi resulted in a significant improvement of FMD (8.2% ± 2.4% vs 6.4% ± 2.3%, P = 0.013). At Year 1 post-PCI, the incidence of major adverse cardiovascular event (MACE) was lower in the allitridi group than that in the control group (10.5% vs 17.2%, P = 0.022). CONCLUSIONS: Allitridi capsules significantly improve the clinical prognosis after PCI in CAD patients with DM. Its mechanism may lies in improved endothelial function and vascular inflammatory state.

Kruppel-like factor 2 might mediate the rapamycin-induced arterial thrombosis in vivo: implications for stent thrombosis in patients.

BACKGROUND: Stent thrombosis is one of severe complications after sirolimus-eluting stent implantation. Rapamycin (sirolimus) promotes arterial thrombosis in in vivo studies. However, the underlying molecular and transcriptional mechanisms of this adverse effect have not been thoroughly investigated. This study was designed to examine the effects of rapamycin on the expression of the gene, Kruppel-like factor 2 (KLF2), and its transcriptional targets in mice. METHODS: Mice were randomly divided into four groups: the control group (intraperitoneal injection with 2.5% of dimethyl sulfoxide (DMSO) only), rapamycin group (intraperitoneal injection with 2 mg/kg of rapamycin only), Ad-LacZ + rapamycin group (carotid arterial incubation with Ad-LacZ plus intraperitoneal injection with 2 mg/kg of rapamycin 10 days later), and Ad-KLF2 + rapamycin group (carotid arterial incubation with Ad-KLF2 plus intraperitoneal injection with 2 mg/kg rapamycin 10 days later). The carotid arterial thrombosis formation was induced by FeCl3 and the time of arterial thrombosis was determined. Finally, the RNA and protein of carotid arteries were extracted for KLF2, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), endothelial nitric oxide synthase (eNOS), thrombomodulin (TM) mRNA and protein analysis. RESULTS: Compared with controls, treatment with rapamycin inhibited KLF2, eNOS and TM mRNA and protein expression, and enhanced TF and PAI-1 mRNA and protein expression, and shortened time to thrombotic occlusion from (1282 ± 347) seconds to (715 ± 120) seconds (P < 0.01) in vivo. Overexpression of KLF2 strongly reversed rapamycin-induced effects on KLF2, eNOS, TM, TF and PAI-1 expression. KLF2 overexpression increased the time to thrombotic occlusion to control levels in vivo. CONCLUSIONS: Rapamycin induced an inhibition of KLF2 expression and an imbalance of anti- and pro-thrombotic gene expression, which promoted arterial thrombosis in vivo. Overexpression of KLF2 increased KLF2 expression and reversed time to thrombosis in vivo.

[Effects of sirolimus upon endothelial thrombotic function of human umbilical vein endothelial cells].

OBJECTIVE: To explore the effects of sirolimus upon endothelial thrombotic function of human umbilical vein endothelial cells (HUVEC). METHODS: Sirolimus was added into the in vitro cultured HUVEC at the concentrations of 0 (control), 0.1, 1 and 10 ng/ml. At 2, 4, 8, 12 and 24 h post-incubation, the cells were harvested for determination of tissue factor (TF), plasminogen activator inhibitor (PAI-1), endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM) expression by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The clotting functions of HUVEC were assayed by an automated coagulation analyzer. RESULTS: Sirolimus induced the expressions of TF and PAI-1 and inhibited the expressions of eNOS and TM in a concentration-dependent manner. The maximal change of mRNA expression was observed at 8 h and remained up to at least 24 h. And the most marked change of protein expression (65% reduction in eNOS expression, 52% reduction in TM, 1.7-fold increase in PAI-1 and 2.8-fold increase in TF) was at 12 h. The clotting time in sirolimus group (89 s ± 9 s) was significantly shorter than that in control group (152 s ± 17 s, P = 0.005). CONCLUSION: Sirolimus induces endothelial antithrombotic dysfunction and shortens the clotting time through an elevated expression of prothrombotic genes TF and PAI-1 and a lowered expression of antithrombotic genes eNOS and TM. It may be one of mechanisms of thrombosis after the implantation of sirolimus-eluting stents.