發(fā)布時間：2018-06-23 03:29

  本文選題：辛伐他汀 + 血小板活化　； 參考：《河北醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的:血栓形成是涉及臨床多種疾病的重要病理生理過程,在心血管疾病領(lǐng)域,特別是在動脈粥樣硬化、冠心病、心肌梗死等疾病的發(fā)生發(fā)展過程中,起著非常重要的作用,常可引起嚴(yán)重危害人類健康的臨床綜合征。在血栓形成過程中,一方面血小板可以通過釋放多種細(xì)胞因子及其類似物促進(jìn)炎癥進(jìn)展,同時也可通過凝血因子相繼酶解激活,瀑布式放大凝血過程,促進(jìn)血栓形成。因此探討血小板活化的機(jī)制及其影響因素,一直是心血管病研究領(lǐng)域的重點(diǎn)和熱點(diǎn)。已有研究發(fā)現(xiàn),血脂升高特別是低密度脂蛋白(low-density lipoprotein,LDL)水平增高與血小板活化密切相關(guān)。羥甲基戊二酰輔酶A(3-hydroxymethyl-3-methylglutaryl coenzyme A,HMG-Co A)還原酶抑制劑(簡稱他汀類藥物)是目前臨床常用的調(diào)脂藥,可通過抑制體內(nèi)膽固醇合成步驟中的限速酶(HMG-Co A還原酶),在調(diào)節(jié)脂質(zhì)代謝過程。多項研究證實(shí),他汀類藥物具有多種療效顯著的抗動脈粥樣硬化作用,其中包括抗血小板作用。近年研究發(fā)現(xiàn),他汀類藥物,特別是脂溶性他汀,如辛伐他汀等,可直接影響血小板功能,抑制血小板激活,并且可獨(dú)立于其降低膽固醇水平之外發(fā)揮上述作用,然而,所涉及的相關(guān)機(jī)制尚不十分明確。過氧化物酶體增值物激活受體(peroxisome proliferator-activated receptors,PPARs)屬于核受體超家族,研究已經(jīng)證實(shí)PPARs激活后通過調(diào)節(jié)脂代謝,脂肪酸氧化及糖代謝平衡等多種機(jī)制發(fā)揮抗炎、延緩動脈粥樣硬化進(jìn)展等作用。而他汀類藥物可作為PPARs的配體,通過激活PPARs,參與調(diào)節(jié)多種病理生理過程。血小板雖然是無核細(xì)胞,但研究發(fā)現(xiàn),在血小板胞漿中三種PPARs亞型(PPARα,PPARβ,PPARγ)均有表達(dá),并可通過非基因調(diào)控途徑影響血小板功能,然而,具體的機(jī)制尚不清楚。目前研究證實(shí),多種誘導(dǎo)劑(如膠原,ADP,花生四烯酸等)可快速激活血小板。當(dāng)血小板活化后,在其表面表達(dá)多種血小板膜糖蛋白(如可溶性P-選擇素,即CD62P;CD40L;CD63等),這些糖蛋白大多存在于靜息血小板胞漿顆粒膜上,當(dāng)血小板活化后,分泌胞漿顆粒,顆粒膜與質(zhì)膜融合,進(jìn)而表達(dá)于血小板表面;此外,血小板活化也可使其原有跨膜糖蛋白發(fā)生構(gòu)象改變(如GPⅡb/Ⅲa),從而促進(jìn)血小板粘附聚集。此外血小板激活后,可引起胞漿內(nèi)鈣離子濃度([Ca2+]i)升高及環(huán)磷酸腺苷(cyclic adenosine monophosphate,c AMP)生成減少,這些都可以反應(yīng)血小板活化狀態(tài)。文獻(xiàn)報道,血小板胞漿c AMP水平升高可通過多種機(jī)制抑制血小板功能,PI3K/Akt及血小板絲裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)信號系統(tǒng)激活與c AMP水平密切相關(guān)。因此,本研究通過探討辛伐他汀體外干預(yù)對膠原誘導(dǎo)的血小板聚集粘附,對血小板活化標(biāo)志物表達(dá)、胞漿內(nèi)鈣離子濃度變化、血小板胞漿c AMP水平、所涉及的PI3K/Akt及血小板MAPKs信號系統(tǒng)的影響,以及血小板胞漿PPARs活化對上述影響的作用,力求從新的角度闡述他汀類藥物抗血小板活化的作用機(jī)制。方法:本研究首先應(yīng)用全血阻抗法探討辛伐他汀對膠原誘導(dǎo)的血小板聚集的作用,并通過ELISA法檢測辛伐他汀對血小板PPARs活化的影響,隨后應(yīng)用全血阻抗法和激光共聚焦技術(shù)探討PPARs活化對辛伐他汀抑制血小板聚集及粘附的影響。此外,利用流式細(xì)胞術(shù)、分光光度法、ELISA法等進(jìn)一步證實(shí)辛伐他汀具有抑制膠原誘導(dǎo)的血小板活化的作用,同時PPARγ激活在辛伐他汀抑制血小板活化中發(fā)揮重要作用。通過應(yīng)用蛋白免疫印跡、免疫共沉淀技術(shù)進(jìn)一步探討辛伐他汀影響膠原誘導(dǎo)的血小板活化所涉及的信號轉(zhuǎn)導(dǎo)通路,以及PPARγ激活對相關(guān)信號傳導(dǎo)通路的影響及作用方式。本研究旨在揭示辛伐他汀對膠原誘導(dǎo)的血小板活化的影響,及PPARs活化的作用,為了解辛伐他汀的抗血小板作用提供新的理論依據(jù)。結(jié)果:我們的研究發(fā)現(xiàn),辛伐他汀體外孵育血小板可激活PPARα及PPARγ,對PPARβ無明顯活化作用。同時,隨著藥物濃度升高,及孵育時間延長,辛伐他汀可呈濃度和時間依賴性的抑制血小板聚集。當(dāng)應(yīng)用PPARα及PPARγ拮抗劑(GW6471,GW9662,終濃度均為10μmol/L)預(yù)孵育全血樣本時,結(jié)果顯示,雖然辛伐他汀具有PPARα及PPARγ雙重激活作用,但是只有PPARγ拮抗劑(GW9662)可以逆轉(zhuǎn)辛伐他汀對膠原誘導(dǎo)的血小板聚集的抑制作用,拮抗PPARα雖有逆轉(zhuǎn)趨勢,但是無統(tǒng)計學(xué)意義。通過采用共聚焦顯微鏡觀察血小板粘附功能,也得到類似的結(jié)論,證實(shí)辛伐他汀可以通過PPARs激活,發(fā)揮抑制血小板粘附的作用,并且,PPARγ活化在其中起主要作用。進(jìn)一步的研究發(fā)現(xiàn),辛伐他汀體外孵育可呈劑量相關(guān)性抑制膠原誘導(dǎo)的血小板CD62p表達(dá)升高(10μmol/L辛伐他汀組49.9%±4.21,30μmol/L辛伐他汀組26.8%±2.89 v.s.陽性對照組74.6%±4.25,P0.05),以及血小板PAC-1表達(dá)升高(10μmol/L辛伐他汀組55.6%±6.01,30μmol/L辛伐他汀組35.3%±4.85 v.s.陽性對照組85.2%±4.16,P0.05)。當(dāng)聯(lián)合PPARs拮抗劑孵育,PPARγ拮抗劑(GW9662)可顯著逆轉(zhuǎn)不同濃度辛伐他汀對血小板CD62p表達(dá)的抑制作用(10μmol/L辛伐他汀聯(lián)合GW9662組62.3%±3.41 v.s.10μmol/L辛伐他汀組49.9%±4.21 P0.05,30μmol/L辛伐他汀聯(lián)合GW9662組37.8%±2.59 v.s.30μmol/L辛伐他汀組26.8%±2.89,P0.05),及對血小板PAC-1表達(dá)的抑制作用(10μmol/L辛伐他汀聯(lián)合GW9662組74.5%±5.68 v.s.10μmol/L辛伐他汀組55.6%±6.01 P0.05,30μmol/L辛伐他汀聯(lián)合GW9662組47.9%±3.85 v.s.30μmol/L辛伐他汀組35.3%±4.85,P0.05),而PPARα拮抗劑(GW6471)未觀察到明顯的逆轉(zhuǎn)作用。類似的結(jié)果也反映在血小板胞漿鈣離子濃度變化上,我們的研究發(fā)現(xiàn),辛伐他汀體外孵育可呈劑量相關(guān)性抑制膠原誘導(dǎo)的血小板胞漿[Ca2+]i升高(3μmol/L辛伐他汀組981±35.62 nmol/L,30μmol/L辛伐他汀組654±43.54 nmol/L,50μmol/L辛伐他汀組392±30.55 nmol/L v.s.陽性對照組1287±50.1 nmol/L,P0.05)。同時,當(dāng)聯(lián)合PPARs拮抗劑孵育,結(jié)果顯示,PPARγ拮抗劑(GW9662)可顯著逆轉(zhuǎn)不同濃度辛伐他汀對血小板胞漿[Ca2+]i升高的抑制作用(3μmol/L辛伐他汀聯(lián)合GW9662組1159±38.62 nmol/L v.s.3μmol/L辛伐他汀組981±35.62 nmol/L P0.05,30μmol/L辛伐他汀聯(lián)合GW9662組989±37.55 nmol/L v.s.30μmol/L辛伐他汀組654±43.54 nmol/L P0.05,50μmol/L辛伐他汀聯(lián)合GW9662組555±37.2 nmol/L v.s.50μmol/L辛伐他汀組392±30.55 nmol/L,P0.05),而PPARα拮抗劑(GW6471)未觀察到明顯的逆轉(zhuǎn)作用。通過對血小板c AMP水平及VASP-Ser157磷酸化的研究也證實(shí),不同濃度辛伐他汀體外孵育可顯著增加血小板c AMP水平(3μmol/L辛伐他汀組9.5±0.36 pmol/m L,30μmol/L辛伐他汀組22.4±0.72 pmol/m L,50μmol/L辛伐他汀組30.5±0.64 pmol/m L v.s.陽性對照組5.2±0.58pmol/m L,P0.05)。而血小板胞漿c AMP是抑制血小板活化的重要因素。同時,血小板c AMP升高可引起VASP Ser 157磷酸化,而辛伐他汀體外孵育可呈劑量依賴性促進(jìn)VASP Ser 157磷酸化,這與其升高血小板c AMP水平作用一致。當(dāng)聯(lián)合PPARs拮抗劑孵育,結(jié)果顯示,PPARγ拮抗劑(GW9662)可顯著逆轉(zhuǎn)不同濃度辛伐他汀對血小板c AMP的升高作用(3μmol/L辛伐他汀聯(lián)合GW9662組7.1±0.54 pmol/m L v.s.3μmol/L辛伐他汀組9.5±0.36 pmol/m L P0.05,30μmol/L辛伐他汀聯(lián)合GW9662組15.4±0.68 pmol/m L v.s.30μmol/L辛伐他汀組22.4±0.72 pmol/m L P0.05,50μmol/L辛伐他汀聯(lián)合GW9662組21.5±0.71 pmol/m L v.s.50μmol/L辛伐他汀組30.5±0.64 pmol/m L,P0.05),而PPARα拮抗劑(GW6471)未觀察到明顯的逆轉(zhuǎn)作用。與之一致的,當(dāng)聯(lián)合GW9662拮抗共同孵育,結(jié)果表面,拮抗PPARγ活性,可逆轉(zhuǎn)辛伐他汀對血小板VASP Ser157磷酸化的抑制作用。通過對相關(guān)信號傳導(dǎo)通路的研究發(fā)現(xiàn),辛伐他汀體外孵育可呈劑量依賴性抑制膠原誘導(dǎo)的血小板胞漿Akt磷酸化,而后者可進(jìn)一步調(diào)控血小板聚集、分泌等多種反應(yīng)。當(dāng)聯(lián)合PPARγ拮抗劑GW9662與辛伐他汀共同孵育,可顯著逆轉(zhuǎn)后者對膠原誘導(dǎo)的血小板Akt磷酸化的抑制作用。此外絲裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)信號傳導(dǎo)通路在血小板活化中具有重要作用,血小板c AMP水平變化及Akt磷酸化與MAPKs信號傳導(dǎo)通路(ERK1/2,p38 MAPK,JNK)活化密切相關(guān)。我們的研究發(fā)現(xiàn),辛伐他汀可呈劑量依賴性抑制膠原誘導(dǎo)的血小板p38 MAPK及ERK1/2磷酸化,而對JNK磷酸化無明顯影響。聯(lián)合PPARγ拮抗劑(GW9662)與辛伐他汀共同孵育,可逆轉(zhuǎn)辛伐他汀對膠原誘導(dǎo)的血小板p38 MAPK及ERK1/2磷酸化的抑制作用。更進(jìn)一步的,通過免疫共沉淀的方法證明,辛伐他汀可呈劑量依賴性的增加膠原誘導(dǎo)的血小板胞漿PPARγ與p38 MAPK及ERK1/2的結(jié)合,結(jié)果表明,辛伐他汀可通過PPARγ與MAPKs(p38 MAPK,ERK1/2)信號通路產(chǎn)生直接相互作用,并可通過此種作用影響MAPK通路(p38MAPK及ERK1/2)磷酸化。結(jié)論：1辛伐他汀具有PPARα及PPAR雙重激活作用,并可呈時間及劑量依賴性抑制膠原誘導(dǎo)的血小板聚集和粘附,PPARγ活化在其中發(fā)揮重要作用。2辛伐他汀主要通過PPARγ活化抑制膠原誘導(dǎo)的血小板活化標(biāo)志物P-選擇素及PAC-1表達(dá),并抑制血小板胞漿[Ca2+]i濃度升高,同時可通過PPARγ活化促進(jìn)血小板c AMP水平及VASP Ser157磷酸化。3辛伐他汀可通過PPARγ活化抑制膠原誘導(dǎo)的血小板Akt磷酸化,及MAPKs(p38 MAPK,ERK1/2)信號傳導(dǎo)通路磷酸化,并且通過PPARγ與p38 MAPK及ERK1/2的直接作用發(fā)揮抑制作用,進(jìn)而影響血小板功能。
[Abstract]:Objective: thrombosis is an important pathophysiological process involved in various clinical diseases. It plays a very important role in the development of cardiovascular diseases, especially in the process of atherosclerosis, coronary heart disease and myocardial infarction. It can often cause serious clinical syndromes which seriously harm human health. In the process of thrombosis, one of the most important diseases is in the process of thrombosis. Platelets can promote the progress of inflammation by releasing a variety of cytokines and their analogues, and can also be activated by successive enzymatic hydrolysis of coagulation factors, and a waterfall type enlargement of coagulation processes to promote thrombus formation. Therefore, the mechanism of platelet activation and its influencing factors have been the focus and hot spot in the research field of cardiovascular disease. It is found that the increase of blood lipid, especially low density lipoprotein (low-density lipoprotein, LDL), is closely related to platelet activation. Hydroxymethylglutamyl two acyl coenzyme A (3-hydroxymethyl-3-methylglutaryl coenzyme A, HMG-Co A) reductase inhibitor (for short, statins) is a commonly used lipid regulating agent, which can be used to inhibit the body bile. The rate limiting enzyme (HMG-Co A reductase) in the step of sterol synthesis regulates the process of lipid metabolism. A number of studies have confirmed that statins have a variety of significant anti atherosclerotic effects, including antiplatelet effects. Recent studies have found that statins, especially fat soluble statins, such as simvastatin, can directly affect blood. The function of the platelets, which inhibits platelet activation, and can be independent of its cholesterol lowering levels, but the related mechanisms are not very clear. The peroxisome activation receptor (peroxisome proliferator-activated receptors, PPARs) belongs to the nuclear receptor superfamily, and the study has confirmed the activation of PPARs. By regulating lipid metabolism, fatty acid oxidation and glucose metabolism balance and other mechanisms to play anti-inflammatory and slow the progression of atherosclerosis, statins can be used as the ligand for PPARs and regulate a variety of pathophysiological processes by activating PPARs. Although platelets are nuclear free cells, three kinds of PPARs in the cytoplasm of platelets have been found. Subtypes (PPAR alpha, PPAR beta, PPAR gamma) are expressed and can affect platelet function through non gene regulatory pathways. However, specific mechanisms are not yet clear. A variety of inducers, such as collagen, ADP, arachidic acid, etc., can quickly activate platelets, and many platelet membrane glycoproteins are expressed on the surface of the blood cells after the activation of the platelets. Soluble P- selectin, that is, CD62P, CD40L, CD63, etc., most of these glycoproteins exist on the resting platelet cytoplasmic granular membrane. When platelets are activated, they secrete cytoplasm particles, granular membranes and plasmalemma, and then express on the surface of the platelets. In addition, platelet activation can also make the original transmembrane glycoproteins conformational changes (such as GP II b/ III a). In addition to platelet activation, platelet activation can cause an increase in intracellular calcium concentration ([Ca2+]i) and a decrease in the formation of cyclic adenosine monophosphate (C AMP), which can reflect the state of platelet activation. It is reported that the elevated level of C AMP in the cytoplasm of platelets can inhibit platelet work through a variety of mechanisms. Yes, the activation of PI3K/Akt and platelet mitogen activated protein kinase (mitogen-activated protein kinases, MAPKs) signal system is closely related to the level of C AMP. Therefore, this study is to explore the platelet aggregation adhesion, expression of platelet activation markers, intracellular calcium concentration changes and blood concentration in vitro by the intervention of simvastatin in vitro. The effect of PI3K/Akt and platelet MAPKs signal system on the level of C AMP, the effect of platelet cytoplasm PPARs activation on the effect of platelets on the above effects, and to elaborate the mechanism of anti platelet activation by statins from a new point of view. The effect of simvastatin on platelet PPARs activation was detected by ELISA method. The effect of PPARs activation on the inhibition of platelet aggregation and adherence by simvastatin was investigated by total blood impedance and laser confocal technique. In addition, the flow cytometry, spectrophotometry, ELISA method, etc. were used to further confirm the simvastatin. It has the effect of inhibiting the activation of collagen induced platelet activation, and PPAR gamma activation plays an important role in simvastatin inhibition of platelet activation. By using protein immunoblotting, immunoblotting is used to further explore the signal transduction pathways involved in the effect of simvastatin on the activation of collagen induced platelets, and the correlation of PPAR gamma activation. This study aims to reveal the effect of simvastatin on the activation of collagen induced platelets and the role of PPARs activation to provide a new theoretical basis for understanding the antiplatelet action of simvastatin. Results: our study found that the platelets of simvastatin can activate PPAR A and PPAR gamma in vitro. There was no obvious activation of PPAR beta. At the same time, with the increase of drug concentration and prolonged incubation time, simvastatin could inhibit platelet aggregation in a concentration and time dependent manner. When using PPAR alpha and PPAR gamma antagonists (GW6471, GW9662, the final concentration of 10 u mol/L) to preincubate whole blood samples, the results showed that although simvastatin had PPAR alpha and PPA R gamma double activation, but only PPAR gamma antagonist (GW9662) can reverse the inhibitory effect of simvastatin on collagen induced platelet aggregation. Although antagonistic PPAR alpha has a reversal trend, there is no statistical significance. A similar conclusion is obtained by using confocal microscopy to observe platelet adhesion function. PPARs activation plays an important role in inhibiting platelet adhesion, and PPAR gamma activation plays a major role. Further studies have found that in vitro incubation of simvastatin can show a dose-dependent inhibition of collagen induced platelet CD62p expression (10 mu mol/L simvastatin group, 49.9% + 4.21,30 mol/L simvastatin group 26.8% + 2.89 v.s. positive control Group 74.6% + 4.25, P0.05), and increased expression of platelet PAC-1 (10 mu mol/L simvastatin group 55.6% + 6.01,30 mol/L simvastatin group 35.3% + 4.85 v.s. positive control group 85.2% + 4.16, P0.05). When combined with PPARs antagonist incubation, PPAR gamma antagonist (GW9662) could significantly reverse the inhibitory effect of different concentration of Simvastatin on platelet CD62p expression (10). Mol/L simvastatin combined with GW9662 group 62.3% + 3.41 v.s.10 mu mol/L simvastatin group 49.9% + 4.21 P0.05,30 micron simvastatin combined with GW9662 group 37.8% + 2.59 v.s.30 mu mol/L simvastatin group 26.8% + 2.89, P0.05), and the inhibitory effect on platelet PAC-1 expression (10 micron mol/L sympletin combined with 74.5% + 5.68. The 55.6% + 6.01 P0.05,30 mu mol/L simvastatin combined with GW9662 group 47.9% + 3.85 v.s.30 mol/L simvastatin group 35.3% + 4.85, P0.05), while PPAR a antagonist (GW6471) did not observe the obvious reversal effect. Similar results were also reflected in the change of platelet cytoplasmic calcium concentration. Our study found that simvastatin can be incubated in vitro. Dose-dependent inhibition of collagen induced platelet cytoplasmic [Ca2+]i increased (3 mu mol/L simvastatin group 981 + 35.62 nmol/L, 30 micron simvastatin group 654 + 43.54 nmol/L, 50 u mol/L simvastatin group 392 + 30.55 nmol/L v.s. positive control group 1287 + 50.1 nmol/L, P0.05). At the same time, when incubated with PPARs antagonist, the results showed that PPAR gamma antagonist (GW9662) the inhibitory effect of different concentrations of simvastatin on the elevation of platelet cytoplasmic [Ca2+]i (3 micron simvastatin combined with GW9662, 1159 + 38.62 nmol/L v.s.3 mu mol/L simvastatin group, 981 + 35.62 nmol/L P0.05,30 micron mol/L simvastatin combined with GW9662 group 989 + 37.55 nmol/L 654 + 43.54 simvastatin group) P0.05,50 mu mol/L simvastatin combined with GW9662 group 555 + 37.2 nmol/L v.s.50 mug mol/L simvastatin group 392 + 30.55 nmol/L, P0.05), but PPAR alpha antagonist (GW6471) did not observe the obvious reversal effect. The level of C AMP (3 mu mol/L simvastatin group was 9.5 + 0.36 pmol/m L, 30 micron simvastatin group 22.4 + 0.72 pmol/m L, 50 micron simvastatin group 30.5 + 0.64 pmol/m L v.s. positive control group 5.2), and platelet cytoplasm was a major factor in inhibiting platelet activation. 157 phosphorylation, while simvastatin incubated in vitro can be dose-dependent to promote VASP Ser 157 phosphorylation, which is consistent with the increase of platelet C AMP level. When combined with PPARs antagonists, the results showed that PPAR gamma antagonist (GW9662) could significantly reverse the effect of different concentrations of simvastatin on the increase of platelet C AMP (3 mu mol/L simvastatin combined. Group GW9662 7.1 + 0.54 pmol/m L v.s.3 mol/L simvastatin group 9.5 + 0.36 pmol/m L P0.05,30 u mol/L simvastatin combined GW9662 group 15.4 + 0.68 pmol/m L 22.4 + 0.72 .05), and PPAR alpha antagonist (GW6471) did not observe a significant reversal effect. When combined with GW9662 antagonism, the antagonism of PPAR gamma activity could reverse the inhibitory effect of simvastatin on the phosphorylation of VASP Ser157 in platelets. Through the study of the related signal transduction pathway, the incubation of simvastatin in vitro can be used as an agent. The amount dependent inhibition of collagen induced phosphorylation of platelet cytoplasm Akt, and the latter can further regulate platelet aggregation, secretion and other reactions. When the combined PPAR gamma antagonist GW9662 is incubated with simvastatin, the latter can significantly reverse the inhibitory effect of the latter on collagen induced platelet Akt phosphorylation. In addition, mitogen activated protein kinase (mitog En-activated protein kinases, MAPKs) signaling pathway plays an important role in platelet activation. The changes in platelet C AMP level and Akt phosphorylation are closely related to the activation of MAPKs signal transduction pathway (ERK1/2, p38 MAPK, JNK). Our study found that simvastatin can be dose-dependent inhibition of collagen induced platelets 1/2 phosphorylation has no significant effect on the phosphorylation of JNK. The co incubation of the combined PPAR gamma antagonist (GW9662) with simvastatin can reverse the inhibitory effect of simvastatin on collagen induced platelet p38 MAPK and ERK1/2 phosphorylation. Further, it is demonstrated by immunoprecipitation that simvastatin can increase collagen induced by a dose-dependent manner. The combination of platelet cytoplasm PPAR gamma and p38 MAPK and ERK1/2 shows that simvastatin can interact directly with the PPAR gamma and MAPKs (p38 MAPK, ERK1/2) signaling pathways and can affect the MAPK pathway (p38MAPK and ERK1/2) phosphorylation through this action. Conclusion: 1 simvastatin has a double activation effect and can be present. Inter and dose-dependent inhibition of collagen induced platelet aggregation and adhesion, PPAR gamma activation plays an important role in.2 simvastatin mainly through PPAR gamma activation to inhibit collagen induced platelet activation marker P- selectin and PAC-1 expression, and inhibit the increase of platelet cytoplasm [Ca2+]i concentration, and can promote blood small by PPAR gamma activation. The level of plate C AMP and VASP Ser157 phosphorylation.3 simvastatin can inhibit collagen induced platelet Akt phosphorylation and MAPKs (p38 MAPK, ERK1/2) signaling pathway phosphorylation through PPAR gamma activation, and inhibit the function of platelets by inhibiting the direct action of PPAR gamma.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R96

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