瑞舒伐他汀对颈动脉粥样硬化斑块的影响及抗炎作用
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摘要
背景和目的：动脉粥样硬化(AS)是缺血性心脑血管疾病的主要病理生理基础。他汀类药物具有显著的抗AS作用。临床方面,ASTEROID研究显示他汀治疗2年能引起粥样硬化斑块的逆转,但近期小样本研究显示,他汀短期内有可能缩小斑块。在细胞和分子水平,基础研究显示,调脂外的抗炎作用,是他汀抗AS的另一重要环节。而且,其上游途径可能有PPARs通路参与,但具体机制不清。本研究旨在：1.应用高分辨率MRI观察瑞舒伐他汀对颈动脉粥样硬化斑块的短期疗效；2.观察瑞舒伐他汀对相关炎症因子的作用；3.初步探讨瑞舒伐他汀对PPARs途径的影响。
方法：1.入选年龄18-75岁,LDL-C 2.6mmol/L-6.5mmol/L;甘油三酯≤4.0mmol／L,有颈动脉粥样硬化斑块,从未使用过他汀类药物的患者20例,瑞舒伐他汀5-20mg／日治疗3月,应用高分辨率MRI检测治疗后斑块、脂核的体积变化,分析其与血脂相关性。2.常规检测血清hsCRP，ELISA法检测血浆MCP-1、VCAM-1水平,荧光定量RT-PCR检测单个核细胞ICAM-1、CCR2的mRNA水平,流式细胞学检测其表达。3.荧光定量RT-PCR检测单个核细胞PPARα、β、γ的mRNA水平,Western blot检测其核内活化蛋白表达。
结果：1.与基线时比较,瑞舒伐他汀治疗后LDL-C、TC、TG水平降低(P<0.05), HDL-C升高不明显(P>0.05)；颈动脉斑块体积、脂核体积均较前缩小。脂核减少的程度和LDL-C减少的幅度成正相关；斑块体积减少的程度与LDL-C、TC减少的幅度均成正相关。
2.瑞舒伐他汀治疗降低患者血中hsCRP、MCP-1的水平(P<0.05),减少单个核细胞CCR2及淋巴细胞表面ICAM-1的表达,对血浆VCAM-1水平及单核细胞表面ICAM-1的表达无影响。
3.瑞舒伐他汀增加单个核细胞PPARα、β的mRNA水平,对PPARγmRNA表达无明显影响；Western blot结果显示,瑞舒伐他汀治疗后三种PPAR的核内活化蛋白均增加(P<0.05)。
结论：1.瑞舒伐他汀具有良好的降脂作用,短期内即可缩小颈动脉粥样硬化斑块,减小脂核,起到稳定斑块的作用。2.瑞舒伐他汀通过减少单个核细胞的相关粘附分子和趋化因子发挥抗炎抗AS作用。3.瑞舒伐他汀抗动脉粥样硬化作用可能与上调单个核细胞PPARs有关,但尚需进一步研究证明。本研究为探讨瑞舒伐他汀的抗动脉粥样硬化机制提供了理论依据。
Objective:Atherosclerosis is the cause of ischemic cerebrovascular disease in pathophysiology. Statins have a significant benifet on prevention and treatment of atherosclerosis.ASTEROID research showed that statin therapy can reverse atherosclerotic plaques. Othervise, recent research from small samples showed that rosuvastatin may regress atherosclerotic plaques in only 1 to 3 months. Other research showed that anti-inflammatory effects of statin beside lipid-lowering,mostly in vitro, is equally important to retarding atherosclerosis. PPARs, which regulate lipid metabolism and inflammatory, probably invlved in the effects of rosuvastatin on atherosclerosis. The purposes of this study were:1. To observe the effects of rosuvastatin on carotid atherosclerotic plaque with high-resolution MRI; 2. to investigate the effects of rosuvastatin on inflammatory factors; 3. to study the relation of rosuvastatin and PPARs.
Methods:1.20 patients without previous statin treatment were enrolled, with age 18 to 75 years-old, LDL-C 2.6mmol/L to 6.5mmol/L, triglyceride less than 4.0mmol/L, coratid plaques with lipid core. Rosuvastatin were given 5 to 20mg/day for 3 months. Both plaque and lipid core volume were examined with high-resolution MRI after rosuvastatin treatment and their correlation were analyzed.2. The levels of hsCRP, MCP-1 and VCAM-1 were examined in serum or plasma. The mRNA and protein expression of ICAM-1 and CCR2 were measured with RT-PCR and flow cytometry, respectively.3. The mRNA and protein expression of PPARs were detected with RT-PCR and Western blot.
Result:1.Compared with the baseline, the levels of LDL-C, TC and TG were decreased after rosuvastatin treatment (P< 0.05). The levels of HDL-C is little higher with no significant (P> 0.05). Both volumes of carotid artery plaques and lipid core were decreased. The correlation between change of lipid core volume and LDL-C decrease was present as well as the reduction of the plaque volume and LDL-C, TC decrease.
2. Rosuvastatin reduced hsCRP and MCP-1 levels(P< 0.05), CCR2 expression on mononuclear cells and ICAM-1 expression on lymphocyts. The effects of rosuvastatin on VCAM-1 level and ICAM-1 expression on monocyte was not be observed.
3. Rosuvastatin improve mRNA and protein expression of PPARa andβ, also increase PPARy protein expression. Otherwise, its effect on PPARy mRNA expression was not significant.
Conclusion:1. The study showed obviously improve on blood lipid profile by rosuvastatin. Regression of atherosclerotic plaques and lipid core also were observed in a short term, which may helpful to plaque stabilization.2. Rosuvastatin exert anti-inflammatory effects through decreasing some adhesion molecules and chemokine on mononuclear cells.3. Upregulation of PPARs levels may relate to the anti-atherosclerosis mechanisms of statin, although further study should be needed. This study may be helpful to further explore rosuvastatin anti-atherosclerosis.
方法：1.入选年龄18-75岁,LDL-C 2.6mmol/L-6.5mmol/L;甘油三酯≤4.0mmol／L,有颈动脉粥样硬化斑块,从未使用过他汀类药物的患者20例,瑞舒伐他汀5-20mg／日治疗3月,应用高分辨率MRI检测治疗后斑块、脂核的体积变化,分析其与血脂相关性。2.常规检测血清hsCRP，ELISA法检测血浆MCP-1、VCAM-1水平,荧光定量RT-PCR检测单个核细胞ICAM-1、CCR2的mRNA水平,流式细胞学检测其表达。3.荧光定量RT-PCR检测单个核细胞PPARα、β、γ的mRNA水平,Western blot检测其核内活化蛋白表达。
结果：1.与基线时比较,瑞舒伐他汀治疗后LDL-C、TC、TG水平降低(P<0.05), HDL-C升高不明显(P>0.05)；颈动脉斑块体积、脂核体积均较前缩小。脂核减少的程度和LDL-C减少的幅度成正相关；斑块体积减少的程度与LDL-C、TC减少的幅度均成正相关。
2.瑞舒伐他汀治疗降低患者血中hsCRP、MCP-1的水平(P<0.05),减少单个核细胞CCR2及淋巴细胞表面ICAM-1的表达,对血浆VCAM-1水平及单核细胞表面ICAM-1的表达无影响。
3.瑞舒伐他汀增加单个核细胞PPARα、β的mRNA水平,对PPARγmRNA表达无明显影响；Western blot结果显示,瑞舒伐他汀治疗后三种PPAR的核内活化蛋白均增加(P<0.05)。
结论：1.瑞舒伐他汀具有良好的降脂作用,短期内即可缩小颈动脉粥样硬化斑块,减小脂核,起到稳定斑块的作用。2.瑞舒伐他汀通过减少单个核细胞的相关粘附分子和趋化因子发挥抗炎抗AS作用。3.瑞舒伐他汀抗动脉粥样硬化作用可能与上调单个核细胞PPARs有关,但尚需进一步研究证明。本研究为探讨瑞舒伐他汀的抗动脉粥样硬化机制提供了理论依据。
Objective:Atherosclerosis is the cause of ischemic cerebrovascular disease in pathophysiology. Statins have a significant benifet on prevention and treatment of atherosclerosis.ASTEROID research showed that statin therapy can reverse atherosclerotic plaques. Othervise, recent research from small samples showed that rosuvastatin may regress atherosclerotic plaques in only 1 to 3 months. Other research showed that anti-inflammatory effects of statin beside lipid-lowering,mostly in vitro, is equally important to retarding atherosclerosis. PPARs, which regulate lipid metabolism and inflammatory, probably invlved in the effects of rosuvastatin on atherosclerosis. The purposes of this study were:1. To observe the effects of rosuvastatin on carotid atherosclerotic plaque with high-resolution MRI; 2. to investigate the effects of rosuvastatin on inflammatory factors; 3. to study the relation of rosuvastatin and PPARs.
Methods:1.20 patients without previous statin treatment were enrolled, with age 18 to 75 years-old, LDL-C 2.6mmol/L to 6.5mmol/L, triglyceride less than 4.0mmol/L, coratid plaques with lipid core. Rosuvastatin were given 5 to 20mg/day for 3 months. Both plaque and lipid core volume were examined with high-resolution MRI after rosuvastatin treatment and their correlation were analyzed.2. The levels of hsCRP, MCP-1 and VCAM-1 were examined in serum or plasma. The mRNA and protein expression of ICAM-1 and CCR2 were measured with RT-PCR and flow cytometry, respectively.3. The mRNA and protein expression of PPARs were detected with RT-PCR and Western blot.
Result:1.Compared with the baseline, the levels of LDL-C, TC and TG were decreased after rosuvastatin treatment (P< 0.05). The levels of HDL-C is little higher with no significant (P> 0.05). Both volumes of carotid artery plaques and lipid core were decreased. The correlation between change of lipid core volume and LDL-C decrease was present as well as the reduction of the plaque volume and LDL-C, TC decrease.
2. Rosuvastatin reduced hsCRP and MCP-1 levels(P< 0.05), CCR2 expression on mononuclear cells and ICAM-1 expression on lymphocyts. The effects of rosuvastatin on VCAM-1 level and ICAM-1 expression on monocyte was not be observed.
3. Rosuvastatin improve mRNA and protein expression of PPARa andβ, also increase PPARy protein expression. Otherwise, its effect on PPARy mRNA expression was not significant.
Conclusion:1. The study showed obviously improve on blood lipid profile by rosuvastatin. Regression of atherosclerotic plaques and lipid core also were observed in a short term, which may helpful to plaque stabilization.2. Rosuvastatin exert anti-inflammatory effects through decreasing some adhesion molecules and chemokine on mononuclear cells.3. Upregulation of PPARs levels may relate to the anti-atherosclerosis mechanisms of statin, although further study should be needed. This study may be helpful to further explore rosuvastatin anti-atherosclerosis.
引文
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[20]Nicholls SJ, Tuzcu EM, Brennan DM, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis:insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)[J]. Circulation,2008,118(24):2506-2514.
[21]王素香,王拥军,尹洪超,等.PAS综合疗法对兔动脉粥样硬化病变的干预[J].中国动脉硬化杂志,2008,16(8)：628-632.
1. Muler WA,Randolph G. Migration of leukocytes across endothelium and beyond Molecules involved in the transmigiration and fate of monocyte.J Leukoc Biol.1999,66:698～704.
2. Raab M,6Daxecker H, Markovic S, et al.Variation of adhesion molecule expression on human umbilical vein endothelial cells upon multiple cytokine application. Clin Chim Acta,2002321:11-16.
3. Ridker PM, Hennekens CH, Roitman-Johnson B, et al.Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet.1998,351:88-92
4. Turhan H, Erbay AR, Yasar AS,et al.Plasma soluble adhesion molecules; intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin levels in patients with isolated coronary artery ectasia. Coron Artery Dis.2005 Feb;16(1):45-50.
5. Daniel T. Price, Joseph Loscalzo. Cellular Adhesion Molecules and Atherogenesis THE AMERICAN JOURNAL OF MEDICINEt,1999,107:85-96
6. Libby P,Ridker PM,Maseri A. Inflammation and atherosclerosis. Circulation 12002,105 (9):1135～1143.
7. NG Chen, F Abbasi, C Lamendola, et al. Mononuclear Cell Adherence to Cultured Endothelium Is Enhanced by Hypertension and Insulin Resistance in Healthy Nondiabetic Volunteers. Healthy Nondiabetic Volunteers. Circulation 1999;100;940-943.
8. S. A. HOPE, I. T. MEREDITH. Cellular adhesion molecules and cardiovascular disease.Part I. Their expression and role in atherogenesis Internal Medicine Journal 2003; 33:380-386.
9. O'Brien, Kevin D, McDonald, Thomas O. BS, Chait Alan,et al.Neovascular Expression of E-Selectin, Intercellular Adhere Vascular Cell Adhesion Molecule-1 in Human Atheroscler Intimal Leukocyte Content Circulation,I 996,93(4),672-682
10. Karaduman M, Sengul A, Oktenli C,et al.Tissue levels of adiponectin, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1 and heart-type fatty acid-binding protein in human coronary atherosclerotic plaques. Clin Endocrinol (Oxf).2006 Feb;64(2):196-202.
11. Carlas T.M, Harlam.J.M. Leukocyte-endothelial adhesion molecules. Blood.1994,84:2068～2101.
12. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes.AmJ Cardiol.2001,88 (8A):10～15.
13. Laura Calabresi; Monica Gomaraschi; Barbara Villa, et al Elevated Soluble Cellular Adhesion Molecules in Subjects With Low HDL-Cholesterol Arteriosclerosis, Thrombosis, and Vascular Biology.2002;22:656-661
14. Young-Cheoul Doo, Sang-Jin Han, Jun-Hee Lee,et al.Associations Among Oxidized Low-Density Lipoprotein Antibody, CReactive Protein, Interleukin-6, and Circulating Cell Adhesion Molecules in Patients With Unstable Angina Pectoris. Am J Cardiol 2004;93:554-558
15. Schmidt C, Hulthe J, Fagerberg BBaseline ICAM-1 and VCAM-1 are increased in initially healthy middle-aged men who develop cardiovascular disease during 6.6 years of follow-up. Angiology.2009,60(1):108-14.
16. Doo YC, Han SJ, Han SW,, et al.Effect of preexisting statin use on expression of C-reactive protein, adhesion molecules, interleukin-6, and antioxidized low-density lipoprotein antibody in patients with unstable angina undergoing coronary stenting. Clin Cardiol.2005 Feb;28(2):72-6.
17. Anne Hackman, Yasunori Abe. Levels of soluble adhesion in patients with dyslipidemia. Circulation.1996,93:1334-1338.
18. Link A,Bohm M,Nickenung G Acute coronary syndrome-better risk tratification by determination of inflammtation parameters ? Med Klin12002,97(2):63-69.
19. Bermudez EA, Ridker PM. C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease. Prev Cardiol12002,5 (1):42～46.
20. Boring L, Gosling J, Cleary M, et al. Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998 Aug 27;394(6696):894-7.
21. S J Connor, N Paraskevopoulos, R Newman, et al.CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease. Gut 2004;53:1287-1294.
22. Carmen Penidol,Maria F. S. Costal, Mariana C. Souza, et al. Involvement of CC chemokines in γ δ T lymphocyte trafficking during allergic inflammation: the role of CCL2/CCR2 pathway. The Japanese Society for Immunology.2007, 20(1):129-139.
23. Romulo Tadeu Dias de Oliveira, Ronei Luciano Mamoni, Jose Roberto Matos Souza, et al. Differential expression of cytokines, chemokines and chemokine receptors in patients with coronary artery disease. International Journal of Cardiology,2009,136(1):17-26.
24. Olof Grip, Sabina Janciauskiene, Stefan Lindgren, et al. Pravastatin down-regulates inflammatory mediators in human monocytes in vitro. European Journal of Pharmacology.2000,410:83-92.
25. O Grip S, Janciauskiene, S Lindgren. Atorvastatin activates PPAR-γ and attenuates the inflammatory response in human monocytes. Inflamm res.2002,51:58-62.
26. Han KH, Ryu J, Hong KH, Ko J,et al. HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo.Circulation. 2005,111(11):1439-1447.
2. Yuan C, Mitsumori LM, Ferguson MS, Polissar NL, Echelard D, Ortiz G,Small R, Davies JW, Kerwin WS, Hatsukami TS. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation. 2001;104:2051-2056.
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[1]Campbell CY, Nasir K, Sarwar A, et al. Combined effect of high low-density lipoprotein cholesterol and metabolic syndrome on subclinical coronary atherosclerosis in white men without clinical evidence of myocardial ischemia[J]. Am J Cardiol,2007, 100(5):840-843.
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[19]Tardif JC, Gregoire J, L'Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis:a randomized controlled trial[J]. JAMA,2007, 297 (15):1675-1682.
[20]Nicholls SJ, Tuzcu EM, Brennan DM, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis:insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)[J]. Circulation,2008,118(24):2506-2514.
[21]王素香,王拥军,尹洪超,等.PAS综合疗法对兔动脉粥样硬化病变的干预[J].中国动脉硬化杂志,2008,16(8)：628-632.
1. Muler WA,Randolph G. Migration of leukocytes across endothelium and beyond Molecules involved in the transmigiration and fate of monocyte.J Leukoc Biol.1999,66:698～704.
2. Raab M,6Daxecker H, Markovic S, et al.Variation of adhesion molecule expression on human umbilical vein endothelial cells upon multiple cytokine application. Clin Chim Acta,2002321:11-16.
3. Ridker PM, Hennekens CH, Roitman-Johnson B, et al.Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet.1998,351:88-92
4. Turhan H, Erbay AR, Yasar AS,et al.Plasma soluble adhesion molecules; intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin levels in patients with isolated coronary artery ectasia. Coron Artery Dis.2005 Feb;16(1):45-50.
5. Daniel T. Price, Joseph Loscalzo. Cellular Adhesion Molecules and Atherogenesis THE AMERICAN JOURNAL OF MEDICINEt,1999,107:85-96
6. Libby P,Ridker PM,Maseri A. Inflammation and atherosclerosis. Circulation 12002,105 (9):1135～1143.
7. NG Chen, F Abbasi, C Lamendola, et al. Mononuclear Cell Adherence to Cultured Endothelium Is Enhanced by Hypertension and Insulin Resistance in Healthy Nondiabetic Volunteers. Healthy Nondiabetic Volunteers. Circulation 1999;100;940-943.
8. S. A. HOPE, I. T. MEREDITH. Cellular adhesion molecules and cardiovascular disease.Part I. Their expression and role in atherogenesis Internal Medicine Journal 2003; 33:380-386.
9. O'Brien, Kevin D, McDonald, Thomas O. BS, Chait Alan,et al.Neovascular Expression of E-Selectin, Intercellular Adhere Vascular Cell Adhesion Molecule-1 in Human Atheroscler Intimal Leukocyte Content Circulation,I 996,93(4),672-682
10. Karaduman M, Sengul A, Oktenli C,et al.Tissue levels of adiponectin, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1 and heart-type fatty acid-binding protein in human coronary atherosclerotic plaques. Clin Endocrinol (Oxf).2006 Feb;64(2):196-202.
11. Carlas T.M, Harlam.J.M. Leukocyte-endothelial adhesion molecules. Blood.1994,84:2068～2101.
12. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes.AmJ Cardiol.2001,88 (8A):10～15.
13. Laura Calabresi; Monica Gomaraschi; Barbara Villa, et al Elevated Soluble Cellular Adhesion Molecules in Subjects With Low HDL-Cholesterol Arteriosclerosis, Thrombosis, and Vascular Biology.2002;22:656-661
14. Young-Cheoul Doo, Sang-Jin Han, Jun-Hee Lee,et al.Associations Among Oxidized Low-Density Lipoprotein Antibody, CReactive Protein, Interleukin-6, and Circulating Cell Adhesion Molecules in Patients With Unstable Angina Pectoris. Am J Cardiol 2004;93:554-558
15. Schmidt C, Hulthe J, Fagerberg BBaseline ICAM-1 and VCAM-1 are increased in initially healthy middle-aged men who develop cardiovascular disease during 6.6 years of follow-up. Angiology.2009,60(1):108-14.
16. Doo YC, Han SJ, Han SW,, et al.Effect of preexisting statin use on expression of C-reactive protein, adhesion molecules, interleukin-6, and antioxidized low-density lipoprotein antibody in patients with unstable angina undergoing coronary stenting. Clin Cardiol.2005 Feb;28(2):72-6.
17. Anne Hackman, Yasunori Abe. Levels of soluble adhesion in patients with dyslipidemia. Circulation.1996,93:1334-1338.
18. Link A,Bohm M,Nickenung G Acute coronary syndrome-better risk tratification by determination of inflammtation parameters ? Med Klin12002,97(2):63-69.
19. Bermudez EA, Ridker PM. C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease. Prev Cardiol12002,5 (1):42～46.
20. Boring L, Gosling J, Cleary M, et al. Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998 Aug 27;394(6696):894-7.
21. S J Connor, N Paraskevopoulos, R Newman, et al.CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease. Gut 2004;53:1287-1294.
22. Carmen Penidol,Maria F. S. Costal, Mariana C. Souza, et al. Involvement of CC chemokines in γ δ T lymphocyte trafficking during allergic inflammation: the role of CCL2/CCR2 pathway. The Japanese Society for Immunology.2007, 20(1):129-139.
23. Romulo Tadeu Dias de Oliveira, Ronei Luciano Mamoni, Jose Roberto Matos Souza, et al. Differential expression of cytokines, chemokines and chemokine receptors in patients with coronary artery disease. International Journal of Cardiology,2009,136(1):17-26.
24. Olof Grip, Sabina Janciauskiene, Stefan Lindgren, et al. Pravastatin down-regulates inflammatory mediators in human monocytes in vitro. European Journal of Pharmacology.2000,410:83-92.
25. O Grip S, Janciauskiene, S Lindgren. Atorvastatin activates PPAR-γ and attenuates the inflammatory response in human monocytes. Inflamm res.2002,51:58-62.
26. Han KH, Ryu J, Hong KH, Ko J,et al. HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo.Circulation. 2005,111(11):1439-1447.