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1.
稳定层流剪应力对内皮细胞骨架调节蛋白VASP表达的影响 总被引:1,自引:0,他引:1
为探讨生理强度的稳定层流剪应力对内皮细胞骨架actin相关蛋白VASP特征影响规律,我们采用胰蛋白酶消化法分离人脐静脉内皮细胞(HUVECs),模拟体内流动环境,建立平行板流动腔模型。利用细胞图像分析系统和ALEXA488—若丹明一次毒蕈环肽双标记法,观察内皮细胞在稳态层流下形态、actin排列变化与VASP分布变化之间的规律。采用Western blot定量动态检测细胞内VASP表达及磷酸化的水平。结果表明,内皮细胞在10dyn/cm^2剪切作用后,随时间细胞逐渐延长,长轴趋于剪应力作用方向排列,细胞与静息态的细胞相比,细胞内骨架沿剪应力方向重组,与此同时VASP表达增强,沿着actin纤维呈点状分布,尤其集中在细胞膜下actin末端区域;Western blot检测显示在剪切后,细胞内VASP出现快速磷酸化,VASP总体表达量增加,2h达高峰后逐渐恢复,8h后再次逐渐升高。以上结果提示血流动力学特性中剪应力引起了细胞胞质内骨架蛋白分子重组,血管内皮细胞形态改变,在此过程中,VASP发挥骨架调节蛋白的作用。 相似文献
2.
3.
Marc Laine Richard Toesca Julie Berbis Corinne Frere Pierre Barnay Michel Pansieri Jean-Pascal Peyre Pierre Michelet Jacques Bessereau Elise Camilleri Olfa Helaf Marjorie Camaleonte Franck Paganelli Françoise Dignat-George Laurent Bonello 《Thrombosis research》2013
Background
The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).Objective
We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.Methods
We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥ 50%.Results
One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17 ± 14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6–22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index < 16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p = 0.9).Conclusion
In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index < 16%. 相似文献4.
Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator‐stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry
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5.
Joseph A. Jakubowski Dominick J. Angiolillo Chunmei Zhou David S. Small Brian A. Moser Jurrien M. ten Berg Patricia B. Brown Stefan James Kenneth J. Winters David Erlinge 《Thrombosis research》2014
Introduction
Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.Materials and Methods
Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.Results
Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01).Conclusions
Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel. 相似文献6.
Schäfer A Burkhardt M Vollkommer T Bauersachs J Münzel T Walter U Smolenski A 《Biochemical pharmacology》2003,65(3):397-405
Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as beta-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser(157) and Ser(239). As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the beta-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser(239) and Ser(157) phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way. 相似文献
7.
《Platelets》2013,24(6):421-428
Peroxynitrite is a potent nitrating and oxidizing agent that exerts differential effects on platelets. In the present study we investigated the influence of peroxynitrite on vasodilator-stimulated phosphoprotein (VASP), a protein that plays a key role in inhibition of platelet adhesion and spreading. In platelets, VASP is a substrate for protein kinase A (PKA), PKC and PKG and phosphorylation by these kinases is thought to block VASP-mediated actin cytoskeletal rearrangement. In the present study, we demonstrate that peroxynitrite phosphorylates VASP by a PKC-dependent mechanism. Peroxynitrite (0–100 µM) induced a concentration and time-dependent increase in phosphorylation of VASP at serine157 (Ser157) and Ser239. Inhibition of soluble guanylyl cyclase (sGC) did not significantly reduce peroxynitrite-mediated phosphorylation, indicating a cGMP-independent pathway for VASP phosphorylation. In contrast nitric oxide-mediated VASP phosphorylation was abolished under conditions of sGC inhibition. Further exploration of the mechanisms underlying VASP phosphorylation indicated a requirement for Ca2+ mobilization, but was independent of protein kinase A, Src kinases and protein nitration. Consistent with previous reports phorbol 12-myristate 13-acetate (PMA; 300 nM) induced phosphorylation of VASP at Ser157, but not Ser239, which was blocked by general protein kinase C (PKC) inhibitors, Ro31-8220 and Bisindolylmaleimide I (BIM-1), and Gö6976, an inhibitor of conventional PKC isoforms. Interestingly, treatment of platelets with these PKC inhibitors significantly reduced peroxynitrite-mediated phosphorylation of both sites, indicating that phosphorylation occurred through PKC-dependent mechanism. Consistent with these findings peroxynitrite caused a small increase in PKC activity as evidenced by increased phosphorylation of PKC substrates. Together these data indicate that peroxynitrite may inhibit platelet function by inducing the phosphorylation of VASP through a mechanism that requires the activation of PKC. 相似文献
8.
Vincenzo Mirone Roberta d’Emmanuele di Villa Bianca Emma Mitidieri Ciro Imbimbo Ferdinando Fusco Paolo Verze Dino F. Vitale Raffaella Sorrentino Giuseppe Cirino 《European urology》2009
Background
Phosphodiesterase 5 inhibitors (PDE5-Is) are a mainstay in the therapy of erectile dysfunction (ED). The primary end point of clinical efficacy, both in clinical studies and normal practice, is represented by the International Index of Erectile Function (IIEF).Objective
To evaluate if platelet cyclic guanosine monophosphate (cGMP) could represent a valuable marker for PDE5-I activity in ED.Design, setting, and participants
The study enrolled 46 patients with psychogenic, organic, and mixed ED (20–71 yr of age; IIEF score <26). Patients were randomized to 6 wk of vardenafil, 5 mg/d at bedtime, or placebo.Intervention
All patients donated two blood samples, one before starting the protocol and the second after 6 wk of treatment.Measurements
Platelet cGMP was measured in both placebo and vardenafil groups. All the patients completed the IIEF-Erectile Function (EF) domain and the sexual encounter profile (SEP) and underwent visual sexual stimulation (VSS) coupled with Rigiscan. All the measurements were performed prior to starting the protocol and after the 6 wk of treatment.Results and limitations
Platelet cGMP production was significantly (p < 0.05) elevated in patients taking 5 mg vardenafil versus placebo. Vardenafil was not superior to placebo in improving IIEF-EF and SEP scores. Conversely, VSS-Rigiscan revealed a significant amelioration (p < 0.028) in the vardenafil group versus placebo. The changes in platelet cGMP level correlated well with VSS-Rigiscan (p = 0.0037) but not with IIEF-EF and SEP.Conclusions
Platelet cGMP could represent a relatively simple, reliable, and objective biomarker of PDE5-I activity in ED clinical studies. Larger clinical studies are needed to further validate the use, utility, and limits of this assay. 相似文献9.
Sirtinol, a cell permeable six-membered lactone ring, is derived from naphthol and potent inhibitor of SIR2 and its naphtholic may have the inhibitory effects on platelets aggregation. In this study, platelet function was examined by collagen/epinephrine (CEPI) and collagen/ADP-induced closure times using the PFA-100 system reveal that CEPI-CT and CADP-CT were prolonged by sirtinol. The platelets aggregation regulated by physiological agonists such as: thrombin, collagen and AA and U46619 were significantly inhibited by sirtinol. Increases cAMP level was observed when sirtinol treated with Prostaglandin E1 in washed platelets. Moreover, sirtinol attenuated intracellular Ca2+ release and thromboxane B2 formation stimulated by thrombin, collagen, AA and U46619 in human washed platelets. This study indicated that sirtinol could inhibit the platelet aggregation induced by physiological agonists, AA and U46619. The mechanism of action may include an increase of cAMP level with enhanced VASP-Ser157 phosphorylation via inhibition of cAMP phosphodiesterase activity and subsequent inhibition of intracellular Ca2+ mobilization, thromboxane A2 formation, and ATP release during the platelet aggregation. 相似文献
10.