阿托伐他汀上调PPARs表达及抑制心脏衰老的研究~1
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摘要
目的:1.观察衰老心脏老化指标的改变,研究阿托伐他汀干预对心脏老化指标的影响。2.检测老年大鼠心脏炎症因子和PPARs基因表达的变化及阿托伐他汀干预的影响。3.分析阿托伐他汀干预对心脏炎症因子表达的影响与PPARs信号转导途径的关系。
方法:1.20个月龄大鼠,给予不同剂量阿托伐他汀(10 mg/kg/d和1 mg/kg/d)灌胃4个月。2.测量各组大鼠的体重、血压、左室壁厚度、血脂水平、心重指数、心肌细胞直径等指标;检测MDA、脂褐素、β半乳糖苷酶、SOD、NOS、CAT等指标的变化;采用苦味酸-天狼猩红染色观察心脏胶原含量;应用TUNEL法检测心肌细胞凋亡情况。3.以RT-PCR和western blot技术检测心肌炎症因子MMP-9、IL-1β、TNF-α在mRNA和蛋白水平的表达。4.以RT-PCR和western blot技术检测心肌PPARα、PPARβ/δ、PPARγ在mRNA和蛋白水平的表达。5.分离培养老年大鼠心肌细胞,给予阿托伐他汀(10μmol/L)和PPARs拮抗剂GW6471、GSK0660、GW9662干预(均为5μmol/L),以RT-PCR和western blot技术检测MMP-9、IL-1β、TNF-α在mRNA和蛋白水平的表达。
结果:1.同青年大鼠相比,老年大鼠的血压、血脂(TG、TC、LDL-C)水平、心重指数、心肌细胞直径、心肌胶原含量、Ⅰ/Ⅲ型胶原比例、心肌细胞凋亡数、脂褐素、β-半乳糖苷酶、MDA含量显著增加(P＜0.01),CAT、NOS、SOD活性显著降低(P＜0.01)。2.与老年对照组相比,他汀组大鼠体重均降低(分别为P＜0.05和P＜0.01),大剂量组更为显著(P＜0.01);与老年对照组相比,他汀组的舒张压均无差异(P＞0.05),大剂量组的收缩压明显降低(P＜0.05),小剂量组无显著差异(P＞0.05);他汀组的心重指数、左室壁厚度和心肌细胞直径、凋亡心肌细胞数均显著低于老年对照组(P＜0.01);他汀组的心肌胶原含量(P＜0.01)及Ⅰ/Ⅲ型胶原比例均低于老年对照组(小剂量组为P＜0.05,大剂量组为P＜0.01),大剂量组的作用更显著(P＜0.05);大剂量组的TG(P＜0.05)、TC(P＜0.01)、LDL-C(P＜0.01)水平均低于老年对照组,小剂量组的TC(P＜0.05)、LDL-C(P＜0.01)水平低于与老年对照组,两个他汀组的HDL-C水平与老年对照组无差异(P＞0.05),大剂量组降低TC和LDL-C的作用较小剂量组更显著(P＜0.05);他汀组的脂褐素、β-半乳糖苷酶、MDA含量较老年对照组均显著降低,CAT、NOS、SOD活性均显著增高(P＜0.01)。3.老年大鼠心肌IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均较青年大鼠显著增加(P＜0.01);他汀组的IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均较老年大鼠显著降低(P＜0.01);大剂量组的作用更显著。4.老年大鼠心肌PPARα、PPARβ/δ和PPARγ三个亚型在mRNA和蛋白水平的表达均较青年组明显降低(P＜0.01);他汀组心肌PPARα、PPARβ/δ和PPARγ三个亚型在mRNA和蛋白水平的表达均较老年大鼠显著增高(P＜0.01)。5.分离培养的老年大鼠心肌细胞的研究中发现,溶剂对照组与空白对照组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均无显著差异(P＞0.05);阿托伐他汀组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均显著低于空白对照组(P＜0.01);PPARs拮抗剂加他汀组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均高于阿托伐他汀组(P＜0.05)。
结论:1.老年大鼠的老化指标如血压、血脂水平,心肌肥厚程度、心肌胶原比例,心肌细胞凋亡数,衰老特异性β-半乳糖苷酶、MDA含量,CAT、NOS、SOD活性等均较青年大鼠有显著改变,阿托伐他汀干预可逆转上述改变。2.老年大鼠心肌炎性因子IL-1β、TNF-α和MMP-9的表达显著增强,阿托伐他汀可抑制上述炎性因子在心肌的表达。3.老年大鼠心肌PPARα、PPARβ/δ和PPARγ三个亚型的表达水平均显著降低,阿托伐他汀干预可上调老年大鼠心肌PPARs三个亚型的表达水平。4.阿托伐他汀抑制老年大鼠心脏炎性因子IL-1β、TNF-α和MMP-9表达的作用机制至少部分与其激活PPARs途径有关。
Objective:1.To investigate the changes of aging rats' heart and the effects of atorvastatin on it.2.To explore the changes of the gene expression of PPARs and inflmammatory factor in myocardium of aging rats and the effects of atorvastatin on it.3.To characterize the role of PPARs pathway in atorvastatin down-regulates the expression of inflammatory factor in myocardum of aging rats.
Methods:1.Wistar rats at 20 month old were given atorvastain(10、1mg/kg/d) for 4 month.2.The changes of body weight,blood pressure,thickness of left ventricle wall,TG,TC,LDL-C,HDL-C,lipofuscin,MDA,β-galactosidase,SOD, CAT,collagen,cadiocyte apoptosis were detected.3.The gene expression of IL-1β,TNF-α,MMP-9 were evalulated by RT-PCR and western blot.4.The gene expression of PPARα,PPARβ/δ,PPARγwere evalulated by RT-PCR and western blot.5.Primary cultures of cadiocyte were got from aging rats.Cadiocyte were treated by atorvastatin,GW6471,GSK0660,GW9662.The gene expression of IL-1β,TNF-α,MMP-9 were evalulated by RT-PCR and western blot.
Results:1.Compared with young rats,the obvious increase were found in blood pressure,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC,LDL-C,β-galactosidase, MDA,lipofuscin(P＜0.01);and obvious decrease were found in SOD,CAT, NOS(P＜0.01).2.There was no difference in diastolic blood pressure between atorvastatin groups and aging group(P＞0.05),systolic blood pressure of high-dose group decreased compared with aging group(P＜0.05).Other targets such as body weight,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC,LDL-C,MDA,lipofuscin, β-galactosidase decreased and SOD,CAT,NOS increased in atovastatin group compared with aging rats.The better effection were found in high-dose group.3. The gene expression of IL-1β,TNF-α,MMP-9 in aging rats increased compared with young rats(P＜0.01).The gene expression of IL-1β,TNF-α,MMP-9 in atorvastatin group decreased compared with aging rats.The better effection were found in high-dose group.4.The gene expression of PPARα,PPARβ/δ,PPARγin aging rats decreased compared with young rats(P＜0.01).The gene expression of PPARα,PPARβ/δ,PPARγin atorvastatin group rats increased compared with aging rats.The better effection were also found in high-dose group.5.The gene expression of IL-1β,TNF-α,MMP-9 in atorvastatin group decreased compared with control group(P＜0.01).The gene expression of IL-1β,TNF-α,MMP-9 in PPARs antagonist plus atorvastatin group increased compared with atorvastatin group(P＜0.05).No difference were found between control group and DMSO group(P＞0.05).
Conlusion:1.There are significant difference in the senescence associated-target, including the blood pressure,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC, LDL-C,MDA,LPS,SOD,CAT,NOS,β-galactosidase between aging and young rats.It can be reverse by atorvastatin treatment.2.The IL-1β,TNF-α,MMP-9 expression in myocardium of aging rats increases compared with young rats and atorvastatin down-regulates it obviously.3.The expression of PPARα,PPARβ/δ, PPARγ,in aging rats decreases remarkably and.atorvastatin up-regulates it obviously.4.Atorvastatin inhibits the expression of inflammatory fator in myocardium of aging rats partly via activation of PPARs signal pathway.
方法:1.20个月龄大鼠,给予不同剂量阿托伐他汀(10 mg/kg/d和1 mg/kg/d)灌胃4个月。2.测量各组大鼠的体重、血压、左室壁厚度、血脂水平、心重指数、心肌细胞直径等指标;检测MDA、脂褐素、β半乳糖苷酶、SOD、NOS、CAT等指标的变化;采用苦味酸-天狼猩红染色观察心脏胶原含量;应用TUNEL法检测心肌细胞凋亡情况。3.以RT-PCR和western blot技术检测心肌炎症因子MMP-9、IL-1β、TNF-α在mRNA和蛋白水平的表达。4.以RT-PCR和western blot技术检测心肌PPARα、PPARβ/δ、PPARγ在mRNA和蛋白水平的表达。5.分离培养老年大鼠心肌细胞,给予阿托伐他汀(10μmol/L)和PPARs拮抗剂GW6471、GSK0660、GW9662干预(均为5μmol/L),以RT-PCR和western blot技术检测MMP-9、IL-1β、TNF-α在mRNA和蛋白水平的表达。
结果:1.同青年大鼠相比,老年大鼠的血压、血脂(TG、TC、LDL-C)水平、心重指数、心肌细胞直径、心肌胶原含量、Ⅰ/Ⅲ型胶原比例、心肌细胞凋亡数、脂褐素、β-半乳糖苷酶、MDA含量显著增加(P＜0.01),CAT、NOS、SOD活性显著降低(P＜0.01)。2.与老年对照组相比,他汀组大鼠体重均降低(分别为P＜0.05和P＜0.01),大剂量组更为显著(P＜0.01);与老年对照组相比,他汀组的舒张压均无差异(P＞0.05),大剂量组的收缩压明显降低(P＜0.05),小剂量组无显著差异(P＞0.05);他汀组的心重指数、左室壁厚度和心肌细胞直径、凋亡心肌细胞数均显著低于老年对照组(P＜0.01);他汀组的心肌胶原含量(P＜0.01)及Ⅰ/Ⅲ型胶原比例均低于老年对照组(小剂量组为P＜0.05,大剂量组为P＜0.01),大剂量组的作用更显著(P＜0.05);大剂量组的TG(P＜0.05)、TC(P＜0.01)、LDL-C(P＜0.01)水平均低于老年对照组,小剂量组的TC(P＜0.05)、LDL-C(P＜0.01)水平低于与老年对照组,两个他汀组的HDL-C水平与老年对照组无差异(P＞0.05),大剂量组降低TC和LDL-C的作用较小剂量组更显著(P＜0.05);他汀组的脂褐素、β-半乳糖苷酶、MDA含量较老年对照组均显著降低,CAT、NOS、SOD活性均显著增高(P＜0.01)。3.老年大鼠心肌IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均较青年大鼠显著增加(P＜0.01);他汀组的IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均较老年大鼠显著降低(P＜0.01);大剂量组的作用更显著。4.老年大鼠心肌PPARα、PPARβ/δ和PPARγ三个亚型在mRNA和蛋白水平的表达均较青年组明显降低(P＜0.01);他汀组心肌PPARα、PPARβ/δ和PPARγ三个亚型在mRNA和蛋白水平的表达均较老年大鼠显著增高(P＜0.01)。5.分离培养的老年大鼠心肌细胞的研究中发现,溶剂对照组与空白对照组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均无显著差异(P＞0.05);阿托伐他汀组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均显著低于空白对照组(P＜0.01);PPARs拮抗剂加他汀组IL-1β、TNF-α和MMP-9的mRNA和蛋白表达水平均高于阿托伐他汀组(P＜0.05)。
结论:1.老年大鼠的老化指标如血压、血脂水平,心肌肥厚程度、心肌胶原比例,心肌细胞凋亡数,衰老特异性β-半乳糖苷酶、MDA含量,CAT、NOS、SOD活性等均较青年大鼠有显著改变,阿托伐他汀干预可逆转上述改变。2.老年大鼠心肌炎性因子IL-1β、TNF-α和MMP-9的表达显著增强,阿托伐他汀可抑制上述炎性因子在心肌的表达。3.老年大鼠心肌PPARα、PPARβ/δ和PPARγ三个亚型的表达水平均显著降低,阿托伐他汀干预可上调老年大鼠心肌PPARs三个亚型的表达水平。4.阿托伐他汀抑制老年大鼠心脏炎性因子IL-1β、TNF-α和MMP-9表达的作用机制至少部分与其激活PPARs途径有关。
Objective:1.To investigate the changes of aging rats' heart and the effects of atorvastatin on it.2.To explore the changes of the gene expression of PPARs and inflmammatory factor in myocardium of aging rats and the effects of atorvastatin on it.3.To characterize the role of PPARs pathway in atorvastatin down-regulates the expression of inflammatory factor in myocardum of aging rats.
Methods:1.Wistar rats at 20 month old were given atorvastain(10、1mg/kg/d) for 4 month.2.The changes of body weight,blood pressure,thickness of left ventricle wall,TG,TC,LDL-C,HDL-C,lipofuscin,MDA,β-galactosidase,SOD, CAT,collagen,cadiocyte apoptosis were detected.3.The gene expression of IL-1β,TNF-α,MMP-9 were evalulated by RT-PCR and western blot.4.The gene expression of PPARα,PPARβ/δ,PPARγwere evalulated by RT-PCR and western blot.5.Primary cultures of cadiocyte were got from aging rats.Cadiocyte were treated by atorvastatin,GW6471,GSK0660,GW9662.The gene expression of IL-1β,TNF-α,MMP-9 were evalulated by RT-PCR and western blot.
Results:1.Compared with young rats,the obvious increase were found in blood pressure,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC,LDL-C,β-galactosidase, MDA,lipofuscin(P＜0.01);and obvious decrease were found in SOD,CAT, NOS(P＜0.01).2.There was no difference in diastolic blood pressure between atorvastatin groups and aging group(P＞0.05),systolic blood pressure of high-dose group decreased compared with aging group(P＜0.05).Other targets such as body weight,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC,LDL-C,MDA,lipofuscin, β-galactosidase decreased and SOD,CAT,NOS increased in atovastatin group compared with aging rats.The better effection were found in high-dose group.3. The gene expression of IL-1β,TNF-α,MMP-9 in aging rats increased compared with young rats(P＜0.01).The gene expression of IL-1β,TNF-α,MMP-9 in atorvastatin group decreased compared with aging rats.The better effection were found in high-dose group.4.The gene expression of PPARα,PPARβ/δ,PPARγin aging rats decreased compared with young rats(P＜0.01).The gene expression of PPARα,PPARβ/δ,PPARγin atorvastatin group rats increased compared with aging rats.The better effection were also found in high-dose group.5.The gene expression of IL-1β,TNF-α,MMP-9 in atorvastatin group decreased compared with control group(P＜0.01).The gene expression of IL-1β,TNF-α,MMP-9 in PPARs antagonist plus atorvastatin group increased compared with atorvastatin group(P＜0.05).No difference were found between control group and DMSO group(P＞0.05).
Conlusion:1.There are significant difference in the senescence associated-target, including the blood pressure,HW/BW,thickness of left ventricle,diameter of cadiocyte,CVF,Ⅰ/Ⅲcollagen ratio,number of apoptosis cadiocyte,TG,TC, LDL-C,MDA,LPS,SOD,CAT,NOS,β-galactosidase between aging and young rats.It can be reverse by atorvastatin treatment.2.The IL-1β,TNF-α,MMP-9 expression in myocardium of aging rats increases compared with young rats and atorvastatin down-regulates it obviously.3.The expression of PPARα,PPARβ/δ, PPARγ,in aging rats decreases remarkably and.atorvastatin up-regulates it obviously.4.Atorvastatin inhibits the expression of inflammatory fator in myocardium of aging rats partly via activation of PPARs signal pathway.
引文
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