5-氨基酮戊酸介导的声动力疗法快速抑制动脉粥样硬化斑块进展
|
摘要
目的研究5-氨基酮戊酸(ALA)介导的声动力疗法(SDT)对动脉粥样硬化斑块的影响。方法球囊损伤加高脂喂养建立兔股动脉粥样硬化斑块模型,荧光显微镜及荧光光谱仪检测静脉注射ALA后0、1、2、3、4、5及6 h(n=3),其代谢产物原卟啉Ⅸ(PpⅨ)在斑块中的代谢与分布。动物随机分为对照组及SDT组。SDT治疗后6、12、24及72 h(n=7),TUNEL及免疫组织化学方法检测斑块中细胞凋亡及巨噬细胞含量;治疗后1周,行高频超声、病理及免疫组织化学检测。结果 ALA注射后2 h,PpⅨ在斑块中含量达到高峰并主要分布在巨噬细胞表达阳性区域。与对照组相比,SDT治疗后6、12、24及72 h斑块中细胞凋亡分别增加3.1、3.8、7.5及4.0倍,SDT治疗后24及72 h斑块中巨噬细胞含量减少45%及67%;与治疗前相比,SDT治疗后1周,股动脉直径狭窄率减少14%。与对照组相比,SDT组斑块面积减小38%,管腔面积增加86%,斑块中脂质、巨噬细胞、增殖期细胞、白细胞介素1β(IL-1β)及肿瘤坏死因子α(TNF-α)含量分别减少64%、71%、76%、62%及60%,胶原含量增加117%,差异均有统计学意义(P<0.05)。结论 ALA-PpⅨ主要分布在动脉粥样硬化斑块的巨噬细胞中;SDT诱导斑块内细胞凋亡,改变斑块内成分促进斑块稳定并减小斑块大小。SDT是一种潜在的无创治疗动脉粥样硬化斑块的方法。
Aim To investigate the effect of aminolaevulinic acid(ALA)-mediated sonodynamic therapy(SDT) on atherosclerosis plaque. Methods The rabbit atherosclerotic model was established by balloon denudation and an atherogenic diet. The metabolism and distribution of protoporphyrin Ⅸ(PpⅨ) in the plaque were detected by fluorescence microscopy and fluorescence spectrometry at 0, 1, 2, 3, 4, 5 and 6 hours after intravenous injection of ALA(n=3). Animals were randomly divided into control group and SDT group. Apoptosis and macrophage content were detected by TUNEL and immunohistochemistry at 6, 12, 24 and 72 hours(n=7) after SDT treatment, and high-frequency ultrasound, pathology and immunohistochemistry were performed at 1 week after SDT treatment. Results Two hours after ALA injection, the content of PpⅨ in plaques reached a peak and mainly distributed in the areas of macrophages. Compared with the control group, the apoptosis of plaque cells increased by 3.1, 3.8, 7.5 and 4.0 folds at 6, 12, 24 and 72 hours after SDT treatment, and the content of macrophages decreased by 45% and 67% at 24 and 72 hours after SDT treatment, and the stenosis rate of femoral artery diameter decreased by 14% at 1 week after SDT treatment. Compared with the control group, the plaque area of SDT group decreased by 38%; the lumen area increased by 86%; the content of lipid, macrophage, proliferative cells, IL-1 beta and TNF-alpha decreased by 64%, 71%, 76%, 62% and 60% respectively; and the content of collagen increased by 117%. Conclusions ALA-PpⅨ is mainly distributed in intraplaque macrophages, SDT induces macrophages apoptosis, and changes the components of plaque to promote plaque stability and reduce the size of plaque. SDT is a potential noninvasive method for the treatment of atherosclerotic plaques.
Aim To investigate the effect of aminolaevulinic acid(ALA)-mediated sonodynamic therapy(SDT) on atherosclerosis plaque. Methods The rabbit atherosclerotic model was established by balloon denudation and an atherogenic diet. The metabolism and distribution of protoporphyrin Ⅸ(PpⅨ) in the plaque were detected by fluorescence microscopy and fluorescence spectrometry at 0, 1, 2, 3, 4, 5 and 6 hours after intravenous injection of ALA(n=3). Animals were randomly divided into control group and SDT group. Apoptosis and macrophage content were detected by TUNEL and immunohistochemistry at 6, 12, 24 and 72 hours(n=7) after SDT treatment, and high-frequency ultrasound, pathology and immunohistochemistry were performed at 1 week after SDT treatment. Results Two hours after ALA injection, the content of PpⅨ in plaques reached a peak and mainly distributed in the areas of macrophages. Compared with the control group, the apoptosis of plaque cells increased by 3.1, 3.8, 7.5 and 4.0 folds at 6, 12, 24 and 72 hours after SDT treatment, and the content of macrophages decreased by 45% and 67% at 24 and 72 hours after SDT treatment, and the stenosis rate of femoral artery diameter decreased by 14% at 1 week after SDT treatment. Compared with the control group, the plaque area of SDT group decreased by 38%; the lumen area increased by 86%; the content of lipid, macrophage, proliferative cells, IL-1 beta and TNF-alpha decreased by 64%, 71%, 76%, 62% and 60% respectively; and the content of collagen increased by 117%. Conclusions ALA-PpⅨ is mainly distributed in intraplaque macrophages, SDT induces macrophages apoptosis, and changes the components of plaque to promote plaque stability and reduce the size of plaque. SDT is a potential noninvasive method for the treatment of atherosclerotic plaques.
引文
[1] Williams KJ,Feig JE,Fisher EA.Rapid regression of atherosclerosis:insights from the clinical and experimental literature[J].Nat Clin Pract Cardiovasc Med,2008,5(2):91-102.
[2] Herrington W,Lacey B,Sherliker P,et al.Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease[J].Circ Res,2016,118(4):535-546.
[3] Brott TG,Howard G,Roubin GS,et al.Long-term results of stenting versus endarterectomy for carotid-artery stenosis[J].N Engl J Med,2016,374(11):1021-1031.
[4] 廖思聪,于杨,王大新,等.动脉粥样硬化中巨噬细胞介导胞葬作用的研究进展[J].中国动脉硬化杂志,2018,26(2):201-206.
[5] Martinet W,Verheye S,De Meyer GR.Selective depletion of macrophages in atherosclerotic plaques via macrophage-specific initiation of cell death[J].Trends Cardiovasc Med,2007,17(2):69-75.
[6] Rosenthal I,Sostaric JZ,Riesz P.Sonodynamic therapy--a review of the synergistic effects of drugs and ultrasound[J].Ultrason Sonochem,2004,11(6):349-363.
[7] Gao Q,Wang F,Guo S,et al.Sonodynamic effect of an anti-inflammatory agent--emodin on macrophages[J].Ultrasound Med Biol,2011,37(9):1478-1485.
[8] Cheng J,Sun X,Guo S,et al.Effects of 5-aminolevulinic acid-mediated sonodynamic therapy on macrophages[J].Int J Nanomedicine,2013,8:669-676.
[9] Li Z,Sun X,Guo S,et al.Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy[J].Thromb Haemost,2015,114(4):793-803.
[10] Krammer B,Plaetzer K.ALA and its clinical impact,from bench to bedside[J].Photochem Photobiol Sci,2008,7(3):283-299.
[11] Peng C,Li Y,Liang H,et al.Detection and photodynamic therapy of inflamed atherosclerotic plaques in the carotid artery of rabbits[J].J Photochem Photobiol B,2011,102(1):26-31.
[12] Waksman R,McEwan PE,Moore TI,et al.Photopoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression[J].J Am Coll Cardiol,2008,52(12):1024-1032.
[13] Trendowski M.The promise of sonodynamic therapy[J].Cancer Metastasis Rev,2014,33(1):143-160.
[14] 王巍,程佳丽,孙鑫,等.5-氨基酮戊酸介导的声动力疗法诱导巨噬细胞和泡沫细胞凋亡[J].中国动脉硬化杂志,2016,24(4):339-344.
[15] Chou R,Dana T,Blazina I,et al.Statins for prevention of cardiovascular disease in adults:evidence report and systematic review for the US preventive services task force[J].JAMA,2016,316(19):2008-2024.
[16] Shapiro MD,Fazio S.From lipids to inflammation:new approaches to reducing atherosclerotic risk[J].Circ Res,2016,118(4):732-749.
[17] Ridker PM,Libby P,MacFadyen JG,et al.Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality:analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)[J].Eur Heart J,2018,39(38):3499-3507.
[18] Nissen SE,Nicholls SJ,Sipahi I,et al.Effect of very high-intensity statin therapy on regression of coronary atherosclerosis:the ASTEROID trial[J].JAMA,2006,295(13):1556-1565.
[19] Nicholls SJ,Ballantyne CM,Barter PJ,et al.Effect of two intensive statin regimens on progression of coronary disease[J].N Engl J Med,2011,365(22):2078-2087.
[20] Takayama T,Hiro T,Yamagishi M,et al.Effect of rosuvastatin on coronary atheroma in stable coronary artery disease:multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS)[J].Circ J,2009,73(11):2110-2117.
[21] Libby P.Inflammation in atherosclerosis[J].Nature,2002,420(6917):868-874.
[22] Moore KJ,Tabas I.Macrophages in the pathogenesis of atherosclerosis[J].Cell,2011,145(3):341-355.
[23] de Vries HE,Moor AC,Dubbelman TM,et al.Oxidized low-density lipoprotein as a delivery system for photosensitizers:implications for photodynamic therapy of atherosclerosis[J].J Pharmacol Exp Ther,1999,289(1):528-534.
[24] Kwok CS,Hulme W,Olier I,et al.Review of early hospitalisation after percutaneous coronary intervention[J].Int J Cardiol,2017,227(1):370-377
[25] Curtis JP,Schreiner G,Wang Y,et al.All-cause readmission and repeat revascularization after percutaneous coronary intervention in a cohort of medicare patients[J].J Am Coll Cardiol,2009,54(10):903-917.
[2] Herrington W,Lacey B,Sherliker P,et al.Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease[J].Circ Res,2016,118(4):535-546.
[3] Brott TG,Howard G,Roubin GS,et al.Long-term results of stenting versus endarterectomy for carotid-artery stenosis[J].N Engl J Med,2016,374(11):1021-1031.
[4] 廖思聪,于杨,王大新,等.动脉粥样硬化中巨噬细胞介导胞葬作用的研究进展[J].中国动脉硬化杂志,2018,26(2):201-206.
[5] Martinet W,Verheye S,De Meyer GR.Selective depletion of macrophages in atherosclerotic plaques via macrophage-specific initiation of cell death[J].Trends Cardiovasc Med,2007,17(2):69-75.
[6] Rosenthal I,Sostaric JZ,Riesz P.Sonodynamic therapy--a review of the synergistic effects of drugs and ultrasound[J].Ultrason Sonochem,2004,11(6):349-363.
[7] Gao Q,Wang F,Guo S,et al.Sonodynamic effect of an anti-inflammatory agent--emodin on macrophages[J].Ultrasound Med Biol,2011,37(9):1478-1485.
[8] Cheng J,Sun X,Guo S,et al.Effects of 5-aminolevulinic acid-mediated sonodynamic therapy on macrophages[J].Int J Nanomedicine,2013,8:669-676.
[9] Li Z,Sun X,Guo S,et al.Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy[J].Thromb Haemost,2015,114(4):793-803.
[10] Krammer B,Plaetzer K.ALA and its clinical impact,from bench to bedside[J].Photochem Photobiol Sci,2008,7(3):283-299.
[11] Peng C,Li Y,Liang H,et al.Detection and photodynamic therapy of inflamed atherosclerotic plaques in the carotid artery of rabbits[J].J Photochem Photobiol B,2011,102(1):26-31.
[12] Waksman R,McEwan PE,Moore TI,et al.Photopoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression[J].J Am Coll Cardiol,2008,52(12):1024-1032.
[13] Trendowski M.The promise of sonodynamic therapy[J].Cancer Metastasis Rev,2014,33(1):143-160.
[14] 王巍,程佳丽,孙鑫,等.5-氨基酮戊酸介导的声动力疗法诱导巨噬细胞和泡沫细胞凋亡[J].中国动脉硬化杂志,2016,24(4):339-344.
[15] Chou R,Dana T,Blazina I,et al.Statins for prevention of cardiovascular disease in adults:evidence report and systematic review for the US preventive services task force[J].JAMA,2016,316(19):2008-2024.
[16] Shapiro MD,Fazio S.From lipids to inflammation:new approaches to reducing atherosclerotic risk[J].Circ Res,2016,118(4):732-749.
[17] Ridker PM,Libby P,MacFadyen JG,et al.Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality:analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)[J].Eur Heart J,2018,39(38):3499-3507.
[18] Nissen SE,Nicholls SJ,Sipahi I,et al.Effect of very high-intensity statin therapy on regression of coronary atherosclerosis:the ASTEROID trial[J].JAMA,2006,295(13):1556-1565.
[19] Nicholls SJ,Ballantyne CM,Barter PJ,et al.Effect of two intensive statin regimens on progression of coronary disease[J].N Engl J Med,2011,365(22):2078-2087.
[20] Takayama T,Hiro T,Yamagishi M,et al.Effect of rosuvastatin on coronary atheroma in stable coronary artery disease:multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS)[J].Circ J,2009,73(11):2110-2117.
[21] Libby P.Inflammation in atherosclerosis[J].Nature,2002,420(6917):868-874.
[22] Moore KJ,Tabas I.Macrophages in the pathogenesis of atherosclerosis[J].Cell,2011,145(3):341-355.
[23] de Vries HE,Moor AC,Dubbelman TM,et al.Oxidized low-density lipoprotein as a delivery system for photosensitizers:implications for photodynamic therapy of atherosclerosis[J].J Pharmacol Exp Ther,1999,289(1):528-534.
[24] Kwok CS,Hulme W,Olier I,et al.Review of early hospitalisation after percutaneous coronary intervention[J].Int J Cardiol,2017,227(1):370-377
[25] Curtis JP,Schreiner G,Wang Y,et al.All-cause readmission and repeat revascularization after percutaneous coronary intervention in a cohort of medicare patients[J].J Am Coll Cardiol,2009,54(10):903-917.