有氧运动降低动脉粥样硬化大鼠血清和组织Lp-PLA2水平及意义
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摘要
目的:脂蛋白相关磷脂酶A2(Lp-PLA2)是一种促动脉粥样硬化(AS)的促炎因子,血清Lp-PLA2的减少可能与运动减轻肥胖的糖脂代谢紊乱有关。但鲜有运动对AS的组织Lp-PLA2水平的影响及意义的研究报道。通过研究4周有氧运动对AS造模大鼠血清和组织(肝、腓肠肌和脂肪)Lp-PLA2水平的影响,探讨Lp-PLA2在运动减轻AS严重程度和糖脂代谢紊乱中的作用。方法:采用腹腔注射维生素D3联合8周高脂饲料喂养的方法建立AS模型大鼠。将建模成功的16只雄性AS大鼠随机分为AS安静组(n=8)和AS运动组(n=8),AS运动组进行4周递增负荷的中等强度有氧运动。同周龄、喂普通饲料的雄性大鼠作为正常对照组(Con组,n=8)。4周运动前、后检测FBG和血脂4项;ELISA检测空腹血清胰岛素(FINS)和血清Lp-PLA2的水平。4周运动后,采用油红O染色和HE染色分别检测主动脉的AS斑块数量、AS程度;免疫组化检测巨噬细胞浸润(CD68),Western blot检测肝、腓肠肌和脂肪组织的Lp-PLA2蛋白水平。结果:1)伴随着脂代谢紊乱(血脂四项异常)、主动脉出现AS改变(大体标本的AS斑块和显微镜下的AS病理变化)和巨噬细胞浸润增加,AS大鼠的血清、肝、腓肠肌和脂肪组织的Lp-PLA2水平比Con组大鼠显著增加;2) 4周有氧运动显著降低了AS大鼠的血清和组织(肝、腓肠肌和脂肪)LpPLA2水平,与此同时,改善了脂代谢紊乱、减少了主动脉的AS斑块数量、减轻主动脉的AS病理改变和巨噬细胞浸润。结论:4周有氧运动减轻AS大鼠的主动脉AS程度和减轻脂代谢紊乱,该作用可能与运动降低AS大鼠血清和肝、腓肠肌、脂肪等组织的Lp-PLA2蛋白水平有关,且减少的Lp-PLA2很可能是通过减轻巨噬细胞浸润来减轻主动脉AS程度。
Object: Lipoprotein-associated phospholipase A2(Lp-PLA2) has become a focus in recent years due to its specific pro-inflammatory effect in atherosclerosis(AS). Some research reports suggest that the decrease of serum Lp-PLA2 might be associated with the improvement of dyslipidemia through aerobic exercise in obesity. Until now, there is still no report about exercise-induced changes of Lp-PLA2 in tissues of AS.So in this study the levels of Lp-PLA2 were detected in multiple tissues(including liver, gastrocnemius and adipose tissue) of AS model rats after 4-week aerobic exercise for exploring the role of Lp-PLA2 in exercise-induced alleviation of AS and improvement of glycolipid metabolism as well as its significance. Method: AS modelrats were established byintraperitoneal injection of Vitamin D3 in combination with 8-week high fat diet feeding. For verifying the successful establishment of AS rats, one rat from Con group and two rats from AS model group were taken randomly to determine the levels of blood glucose and lipid as well as morphological and pathological alterations of the aorta. Then, 16 successfully established AS rats were randomly divided into AS group(n=8) and exercised AS group(EAS, n=8). EAS group rats did 4-week moderate intensity aerobic exercise on treadmill with gradually increasing intensity while Con and AS rats kept sedentary life, with allof the rats were fed with common diet during the experiments. Before and after 4-week exercise, the blood of the three group rats were drawn to measure the circulating levels of fasting blood glucose(FBG), triglyceride(TC), total cholesterol(TG), LDLand HDL.The fasting insulin(FINS) and serum Lp-PLA2 were measured by ELISA.The rats were anaesthetized and sacrificed after 4-week exercise, and the liver, gastrocnemius and perirenal fat of the rats were collected to detect the protein levels of Lp-PLA2(Western blot), and the full-length aorta of the rats were separated to determine AS arteriosclerosis plaque(oil red O staining and histopathological examination) and macrophages infiltration(immunohistochemistry). Results: 1) Compared with the Con rats, the levels of serum Lp-PLA2 and the protein levels of Lp-PLA2 in the livers, gastrocnemius and adipose tissues of AS rats were significant increased, accompanied with the disorders of glucose and lipid metabolism(increases of TC, TG, LDL and FINS as well as decrease of HDL, but unchanged FBG), appearances of atherosclerotic plaques and atherosclerotic pathological characteristic in aorta as well as enhancement of macrophage infiltration in aorta(reflected by increase of macrophage-specific marker CD68). 2) The levels of serum Lp-PLA2 and protein levels of Lp-PLA2 in the livers, gastrocnemius and adipose tissues of AS rats were significantly decreased by 4-week aerobic exercise, accompanied withthe improvement of glucose and lipid metabolism, alleviation of atherosclerotic plaques and atherosclerotic pathological characteristic in aorta as well as reduction of macrophage infiltration in aorta. Conclusions: These results suggested that the beneficial effects of exercise on reducing the severity of AS in aorta and improving the disorder of glucose and lipid metabolism in AS rats might be related to the decrease of Lp-PLA2 in serumand multiply tissues(livers, gastrocnemius and adipose tissues) of AS rats. Furthermore, the reduced Lp-PLA2 was likely to alleviate the severity of aortic atherosclerosis by reducing macrophage infiltration.
Object: Lipoprotein-associated phospholipase A2(Lp-PLA2) has become a focus in recent years due to its specific pro-inflammatory effect in atherosclerosis(AS). Some research reports suggest that the decrease of serum Lp-PLA2 might be associated with the improvement of dyslipidemia through aerobic exercise in obesity. Until now, there is still no report about exercise-induced changes of Lp-PLA2 in tissues of AS.So in this study the levels of Lp-PLA2 were detected in multiple tissues(including liver, gastrocnemius and adipose tissue) of AS model rats after 4-week aerobic exercise for exploring the role of Lp-PLA2 in exercise-induced alleviation of AS and improvement of glycolipid metabolism as well as its significance. Method: AS modelrats were established byintraperitoneal injection of Vitamin D3 in combination with 8-week high fat diet feeding. For verifying the successful establishment of AS rats, one rat from Con group and two rats from AS model group were taken randomly to determine the levels of blood glucose and lipid as well as morphological and pathological alterations of the aorta. Then, 16 successfully established AS rats were randomly divided into AS group(n=8) and exercised AS group(EAS, n=8). EAS group rats did 4-week moderate intensity aerobic exercise on treadmill with gradually increasing intensity while Con and AS rats kept sedentary life, with allof the rats were fed with common diet during the experiments. Before and after 4-week exercise, the blood of the three group rats were drawn to measure the circulating levels of fasting blood glucose(FBG), triglyceride(TC), total cholesterol(TG), LDLand HDL.The fasting insulin(FINS) and serum Lp-PLA2 were measured by ELISA.The rats were anaesthetized and sacrificed after 4-week exercise, and the liver, gastrocnemius and perirenal fat of the rats were collected to detect the protein levels of Lp-PLA2(Western blot), and the full-length aorta of the rats were separated to determine AS arteriosclerosis plaque(oil red O staining and histopathological examination) and macrophages infiltration(immunohistochemistry). Results: 1) Compared with the Con rats, the levels of serum Lp-PLA2 and the protein levels of Lp-PLA2 in the livers, gastrocnemius and adipose tissues of AS rats were significant increased, accompanied with the disorders of glucose and lipid metabolism(increases of TC, TG, LDL and FINS as well as decrease of HDL, but unchanged FBG), appearances of atherosclerotic plaques and atherosclerotic pathological characteristic in aorta as well as enhancement of macrophage infiltration in aorta(reflected by increase of macrophage-specific marker CD68). 2) The levels of serum Lp-PLA2 and protein levels of Lp-PLA2 in the livers, gastrocnemius and adipose tissues of AS rats were significantly decreased by 4-week aerobic exercise, accompanied withthe improvement of glucose and lipid metabolism, alleviation of atherosclerotic plaques and atherosclerotic pathological characteristic in aorta as well as reduction of macrophage infiltration in aorta. Conclusions: These results suggested that the beneficial effects of exercise on reducing the severity of AS in aorta and improving the disorder of glucose and lipid metabolism in AS rats might be related to the decrease of Lp-PLA2 in serumand multiply tissues(livers, gastrocnemius and adipose tissues) of AS rats. Furthermore, the reduced Lp-PLA2 was likely to alleviate the severity of aortic atherosclerosis by reducing macrophage infiltration.
引文
范艳平,李海滨,谭清武,等,2016.人血浆脂蛋白相关磷脂酶A2在冠状动脉粥样硬化中的研究进展[J].临床误诊误治,29(6):110-113.
贺强,季浏,2016.一次急性耐力游泳运动对DIO小鼠脂肪组织巨噬细胞介导的慢性炎症的影响[J].北京体育大学学报,39(2):61-68.
李同达,曹洪欣,徐慧,等,2013.冠状动脉粥样硬化大鼠实验动物模型的改进与评价[J].中国实验动物学报,21(6):32-36.
孙焱,郝选明,耿青青,等,2012.有氧运动对apoE基因缺陷小鼠主动脉脂质斑块面积及血清炎症相关细胞因子水平的影响[J].北京体育大学学报,35(4):53-58.
孙焱,郝选明,耿青青,等,2014.有氧运动改善动脉粥样硬化病变的抗炎机制研究[J].北京体育大学学报,37(4):62-67.
张海平,吴翊馨,2007.动脉粥样硬化模型大鼠接受有氧运动后的组织学变化[J].中国组织工程研究与临床康复,2(45):9051-9055.
中国老年学学会心脑血管病专业委员会,中国医师协会检验医师分会心脑血管病专家委员会,2015.脂蛋白相关的磷脂酶A2临床应用中国专家建议[J].中国医药导刊,17(11):1154.
BRAAM K I,VANDER TORRE P,TAKKEN T,et al.,2016.Physical exercise training interventions for children and young adults during and after treatment for childhood cancer[J].Cochrane Db Syst Rev,3:CD008796.
CAI A,ZHENG D,QIU R,et al.,2013.Lipoprotein-associated phospholipase A2(Lp-PLA(2)):A novel and promising biomarker for cardiovascular risks assessment[J].Dis Markers,34(5):323-331.
CHERNYAVSKIY I,VEERANKI S,SEN U,et al.,2016.Atherogenesis:hyperhomocysteinemia interactions with LDL,macrophage function,paraoxonase 1,and exercise[J].Ann N Y Acad Sci,1363:138-154.
DOUGLAS G R,BROWN A J,GILLARD J H,et al.,2017.Impact of fiber structure on the material stability and rupture mechanisms of coronary atherosclerotic plaques[J].Ann Biomed Eng,45(6):1462-1474.
FENNING R S,BURGERT M E,HAMAMDZIC D,et al.,2015.Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2[J].J Am Heart Assoc,4(2):1-12.
FULLER K N Z,SUMMERS C M,VALENTINE R J,2017.Effect of a single bout of aerobic exercise on high-fat meal-induced inflammation[J].Metabolism,71:144-152.
GARG P K,NORBY F L,POLFUS L M,et al.,2018.Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease:Findings from the atherosclerosis risk in communities study(ARIC)[J].Atherosclerosis,268:12-18.
GE P C,CHEN Z H,PAN R Y,et al.,2016.Synergistic effect of lipoprotein-associated phospholipase A2 with classical risk factors on coronary heart disease:A multi-ethnic study in china[J].Cell Physiol Biochem,40(5):953-968.
KATSIMPOULAS M,KADOGLOU N E,MOUSTARDAS P,et al.,2016.The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice[J].Hellenic J Cardiol,57(6):417-425.
KAWANISHI N,NIIHARA H,MIZOKAMI T,et al.,2015.Exercise training attenuates neutrophil infiltration and elastase expression in adipose tissue of high-fat-diet-induced obese mice[J].Physiol Rep,3(9):e12534.
KELESOGLU M,KIZILAY F,BARUTCUOGLU B,et al.,2018.The relationship between lipoprotein-associated phospholipase A2 with cardiovascular risk factors in testosterone deficiency[J].Turk JUrol,44(2):103-108.
KOH Y,PARK J,CARTER R,2018.Oxidized Low-Density Lipoprotein and Cell Adhesion Molecules Following Exercise Training[J].Int J Sports Med,39(2):83-88.
LIN X J,YIN L,WANG X H,2016.Decrease of circulatory level of inflammatory factor Lp-PLA2 by short-term aerobic exercise in obese female juveniles[J].Adapt Med,8(1):6-11.
MAIOLINO G,BISOQNI V,ROSSITTO G,et al.,2015.Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications[J].World J Cardiol,7(10):609-620.
MAYER O J R,SEIDLEROVA J,FILIPOVSKY J,et al.,2014.Unexpected inverse relationship between impaired glucose metabolism and lipoprotein-associated phospholipase A2 activity in patients with stable vascular disease[J].Eur J Intern Med,25(6):556-560.
MOUSTARDAS P,KADOGLOU N P,KATSIMPOULAS M,et al.,2014.The complementary effects of atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in ApoE knockout mice[J].PloS one,9(9):e108240.
NELSON T L,BIGGS M L,KIZER J R,et al.,2012.Lipoprotein-associated phospholipase A2(Lp-PLA2)and future risk of type 2diabetes:Results from the Cardiovascular Health Study[J].J Clin Endocrinol Metab,97(5):1695-1701.
OKABE T A,SHIMADA K,HATTORI M,et al.,2007.Swimming reduces the severity of atherosclerosis in apolipoprotein E deficient mice by antioxidant effects[J].Cardiovasc Res,74(3):537-545.
OLZA J,AGUILERA C M,GIL-CAMPOS M,et al.,2015.A Continuous metabolic syndrome score is associated with specific biomarkers of inflammation and CVD risk in prepubertal children[J].Ann Nutr Metab,66(2-3):72-79.
THOMPSON D,WALHIN J P,BATTERHAM A M,et al.,2014.Effect of diet or diet plus physical activity versus usual care on inflammatory markers in patients with newly diagnosed type 2 diabetes:The Early ACTivity in Diabetes(ACTID)randomized,controlled trial[J].J Am Heart Assoc,3(3):e000828.
UESHIMA H,KADOWAKI T,HISAMATSU T,et al.,2016.Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population[J].Atherosclerosis,246:141-147.
VERONA J,GILLIGAN L E,GIMENEZ C,et al.,2013.Physical activity and cardiometabolic risk in male children and adolescents:The Balcarce study[J].Life Sci,93(2-3):64-68.
WANG C,FANG X,HUA Y,et al.,2018.Lipoprotein-associated phospholipase A2 and risk of carotid atherosclerosis and cardiovascular events in community-based older adults in china[J].Angiology,69(1):49-58.
WEI L,KE Z,ZHAO Y,et al.,2017.The elevated lipoprotein-associated phospholipase A2 activity is associated with the occurrence and recurrence of acute cerebral infarction[J].Neuroreport28(6):325-330.
WOOTEN J S,NAMBI P,GILLARD B K,et al.,2013.Intensive lifestyle modification reduces Lp-PLA2 in dyslipidemic HIV_HAARTpatients[J].Med Sci Sports Exerc,45(6):1043-1050.
WU W,WANG H,JIAO G,et al.,2017.Aerobic exercise suppresses atherosclerosis through adiponectin-nuclear transcription factor kappaB pathway in apolipoprotein E-deficient mice[J].Am J Med Sci,353(3):275-281.
YANG L,CONG H L,WANG S F,et al.,2017.AMP-activated protein kinase mediates the effects of lipoprotein-associated phospholipase A2 on endothelial dysfunction in atherosclerosis[J].Exp Ther Med,13(4):1622-1629.
YOUNUS A,HUMAYUN C,AHMAD R,et al.,2017.Lipoprotein-associated phospholipase A2 and its relationship with markers of subclinical cardiovascular disease:A systematic review[J].J Clin Lipidol,11(2):328-337.
ZHANG J,XU D L,LIU X B,et al.,2016.Darapladib,a Lipoprotein-Associated Phospholipase A2 Inhibitor,Reduces Rho Kinase Activity in Atherosclerosis[J].Yonsei Med J,57(2):321-327.
ZLATOHLAVEK L,HUBACEK J A,VRABLIK M,et al.,2015.The impact of physical activity and dietary measures on the biochemical and anthropometric parameters in obese children.Is there any genetic predisposition?[J].Cent Eur J Public Health,23(suppl):S62-S66.
贺强,季浏,2016.一次急性耐力游泳运动对DIO小鼠脂肪组织巨噬细胞介导的慢性炎症的影响[J].北京体育大学学报,39(2):61-68.
李同达,曹洪欣,徐慧,等,2013.冠状动脉粥样硬化大鼠实验动物模型的改进与评价[J].中国实验动物学报,21(6):32-36.
孙焱,郝选明,耿青青,等,2012.有氧运动对apoE基因缺陷小鼠主动脉脂质斑块面积及血清炎症相关细胞因子水平的影响[J].北京体育大学学报,35(4):53-58.
孙焱,郝选明,耿青青,等,2014.有氧运动改善动脉粥样硬化病变的抗炎机制研究[J].北京体育大学学报,37(4):62-67.
张海平,吴翊馨,2007.动脉粥样硬化模型大鼠接受有氧运动后的组织学变化[J].中国组织工程研究与临床康复,2(45):9051-9055.
中国老年学学会心脑血管病专业委员会,中国医师协会检验医师分会心脑血管病专家委员会,2015.脂蛋白相关的磷脂酶A2临床应用中国专家建议[J].中国医药导刊,17(11):1154.
BRAAM K I,VANDER TORRE P,TAKKEN T,et al.,2016.Physical exercise training interventions for children and young adults during and after treatment for childhood cancer[J].Cochrane Db Syst Rev,3:CD008796.
CAI A,ZHENG D,QIU R,et al.,2013.Lipoprotein-associated phospholipase A2(Lp-PLA(2)):A novel and promising biomarker for cardiovascular risks assessment[J].Dis Markers,34(5):323-331.
CHERNYAVSKIY I,VEERANKI S,SEN U,et al.,2016.Atherogenesis:hyperhomocysteinemia interactions with LDL,macrophage function,paraoxonase 1,and exercise[J].Ann N Y Acad Sci,1363:138-154.
DOUGLAS G R,BROWN A J,GILLARD J H,et al.,2017.Impact of fiber structure on the material stability and rupture mechanisms of coronary atherosclerotic plaques[J].Ann Biomed Eng,45(6):1462-1474.
FENNING R S,BURGERT M E,HAMAMDZIC D,et al.,2015.Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2[J].J Am Heart Assoc,4(2):1-12.
FULLER K N Z,SUMMERS C M,VALENTINE R J,2017.Effect of a single bout of aerobic exercise on high-fat meal-induced inflammation[J].Metabolism,71:144-152.
GARG P K,NORBY F L,POLFUS L M,et al.,2018.Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease:Findings from the atherosclerosis risk in communities study(ARIC)[J].Atherosclerosis,268:12-18.
GE P C,CHEN Z H,PAN R Y,et al.,2016.Synergistic effect of lipoprotein-associated phospholipase A2 with classical risk factors on coronary heart disease:A multi-ethnic study in china[J].Cell Physiol Biochem,40(5):953-968.
KATSIMPOULAS M,KADOGLOU N E,MOUSTARDAS P,et al.,2016.The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice[J].Hellenic J Cardiol,57(6):417-425.
KAWANISHI N,NIIHARA H,MIZOKAMI T,et al.,2015.Exercise training attenuates neutrophil infiltration and elastase expression in adipose tissue of high-fat-diet-induced obese mice[J].Physiol Rep,3(9):e12534.
KELESOGLU M,KIZILAY F,BARUTCUOGLU B,et al.,2018.The relationship between lipoprotein-associated phospholipase A2 with cardiovascular risk factors in testosterone deficiency[J].Turk JUrol,44(2):103-108.
KOH Y,PARK J,CARTER R,2018.Oxidized Low-Density Lipoprotein and Cell Adhesion Molecules Following Exercise Training[J].Int J Sports Med,39(2):83-88.
LIN X J,YIN L,WANG X H,2016.Decrease of circulatory level of inflammatory factor Lp-PLA2 by short-term aerobic exercise in obese female juveniles[J].Adapt Med,8(1):6-11.
MAIOLINO G,BISOQNI V,ROSSITTO G,et al.,2015.Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications[J].World J Cardiol,7(10):609-620.
MAYER O J R,SEIDLEROVA J,FILIPOVSKY J,et al.,2014.Unexpected inverse relationship between impaired glucose metabolism and lipoprotein-associated phospholipase A2 activity in patients with stable vascular disease[J].Eur J Intern Med,25(6):556-560.
MOUSTARDAS P,KADOGLOU N P,KATSIMPOULAS M,et al.,2014.The complementary effects of atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in ApoE knockout mice[J].PloS one,9(9):e108240.
NELSON T L,BIGGS M L,KIZER J R,et al.,2012.Lipoprotein-associated phospholipase A2(Lp-PLA2)and future risk of type 2diabetes:Results from the Cardiovascular Health Study[J].J Clin Endocrinol Metab,97(5):1695-1701.
OKABE T A,SHIMADA K,HATTORI M,et al.,2007.Swimming reduces the severity of atherosclerosis in apolipoprotein E deficient mice by antioxidant effects[J].Cardiovasc Res,74(3):537-545.
OLZA J,AGUILERA C M,GIL-CAMPOS M,et al.,2015.A Continuous metabolic syndrome score is associated with specific biomarkers of inflammation and CVD risk in prepubertal children[J].Ann Nutr Metab,66(2-3):72-79.
THOMPSON D,WALHIN J P,BATTERHAM A M,et al.,2014.Effect of diet or diet plus physical activity versus usual care on inflammatory markers in patients with newly diagnosed type 2 diabetes:The Early ACTivity in Diabetes(ACTID)randomized,controlled trial[J].J Am Heart Assoc,3(3):e000828.
UESHIMA H,KADOWAKI T,HISAMATSU T,et al.,2016.Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population[J].Atherosclerosis,246:141-147.
VERONA J,GILLIGAN L E,GIMENEZ C,et al.,2013.Physical activity and cardiometabolic risk in male children and adolescents:The Balcarce study[J].Life Sci,93(2-3):64-68.
WANG C,FANG X,HUA Y,et al.,2018.Lipoprotein-associated phospholipase A2 and risk of carotid atherosclerosis and cardiovascular events in community-based older adults in china[J].Angiology,69(1):49-58.
WEI L,KE Z,ZHAO Y,et al.,2017.The elevated lipoprotein-associated phospholipase A2 activity is associated with the occurrence and recurrence of acute cerebral infarction[J].Neuroreport28(6):325-330.
WOOTEN J S,NAMBI P,GILLARD B K,et al.,2013.Intensive lifestyle modification reduces Lp-PLA2 in dyslipidemic HIV_HAARTpatients[J].Med Sci Sports Exerc,45(6):1043-1050.
WU W,WANG H,JIAO G,et al.,2017.Aerobic exercise suppresses atherosclerosis through adiponectin-nuclear transcription factor kappaB pathway in apolipoprotein E-deficient mice[J].Am J Med Sci,353(3):275-281.
YANG L,CONG H L,WANG S F,et al.,2017.AMP-activated protein kinase mediates the effects of lipoprotein-associated phospholipase A2 on endothelial dysfunction in atherosclerosis[J].Exp Ther Med,13(4):1622-1629.
YOUNUS A,HUMAYUN C,AHMAD R,et al.,2017.Lipoprotein-associated phospholipase A2 and its relationship with markers of subclinical cardiovascular disease:A systematic review[J].J Clin Lipidol,11(2):328-337.
ZHANG J,XU D L,LIU X B,et al.,2016.Darapladib,a Lipoprotein-Associated Phospholipase A2 Inhibitor,Reduces Rho Kinase Activity in Atherosclerosis[J].Yonsei Med J,57(2):321-327.
ZLATOHLAVEK L,HUBACEK J A,VRABLIK M,et al.,2015.The impact of physical activity and dietary measures on the biochemical and anthropometric parameters in obese children.Is there any genetic predisposition?[J].Cent Eur J Public Health,23(suppl):S62-S66.