摘要
目的：探讨瑞舒伐他汀对大鼠急性心肌梗死后心功能、心室重构和肌球蛋白重链、基质金属蛋白酶2、金属蛋白酶组织抑制因子2表达的影响。
方法：取60只SD大鼠,随机分为假手术(不结扎冠状动脉)组(S组n=10)和急性心肌梗死(结扎左冠状动脉前降支)组(n=50)。将急性心肌梗死模型制模成功24h后存活的36只大鼠再随机分成瑞舒伐他汀(灌胃瑞舒伐他汀lOmg/kg·d)组(R组n=18)和心肌梗死对照组(M组n=18)。假手术组和心肌梗死对照组每日给以等量生理盐水灌胃。8周后各组存活大鼠行血生化检查、超声心动图及血流动力学测定。处死大鼠,取出心脏测定左室重量指数(LVWI)、左室长轴径(LVLA)、心肌细胞横截面积(CSA),苦味酸-天狼猩红染色测定非梗死区Ⅰ型、Ⅲ型心肌胶原含量,TUNEL法检测非梗死区心肌细胞凋亡指数,应用反转录-聚合酶链反应法检测非梗死区基质金属蛋白酶2(MMP-2)、金属蛋白酶组织抑制因子2(TIMP-2)及心肌肌球蛋白重链(MHC)的表达,免疫组化分析基质金属蛋白酶2(MMP-2)、金属蛋白酶组织抑制因子2 (TIMP-2)在非梗死区的蛋白表达。
结果：
1.各组间血脂、天门冬氨酸转氨酶(AST)、肌酐(Cr)、肌酸激酶(CK)水平差异无统计学意义(P>0.05)。
2.与假手术组相比,心梗对照组及治疗组LVAWT变薄(0.11±0.03mm、0.13±0.02mm vs 0.18±0.02mm,P<0.05),LVPWT变厚(0.24±0.03mm、0.22±0.02mmvs 0.18±0.02mm,P<0.05),左室舒张末内径(LVEDD)增高(0.61±0.06mm、0.51±0.06mm vs 0.39±0.06mm,P<0.05)、短轴缩短率(LVFS)和射血分数(LVEF)降低(0.23±0.05、0.39±0.06 vs 0.58±0.06,P<0.05；0.34±0.06、0.45±0.05 vs 0.71±0.06,P<0.05)；与心梗对照组比较,治疗组LVAWT变厚(0.13±0.02mm vs 0.11±0.03mm,P>0.05),LVPWT变薄(0.22±0.02mm vs 0.24±0.03mm,P>0.05),左室舒张末内径(LVEDD)降低(0.51±0.06mm vs 0.61±0.06mm,P<0.05)、短轴缩短率(LVFS)和射血分数(LVEF)增高(0.39±0.06vs 0.23±0.05,P<0.05；0.45±0.05 vs 0.34±0.06,P<0.05)。
3.与假手术组相比,心梗对照组及治疗组术后8周左室收缩压(LVSP)、左室内压最大上升下降速率(±dp/dtmax)显著减低(70±6mmHg.109±11mmHg vs 149±13mmHg,P<0.01；2959±252mmHg/s.4050±193mmHg/s vs 6162±199mHg/s,P<0.01；3159±190mmHg/s.3991±199mmHg/s vs 5153±209mmHg／s,P<0.01),左室舒张末压(LVEDP)显著增高(26±5mmHg、13±3mmHg vs 3±1mmHg,P<0.01)；与心梗对照比较,治疗组左室收缩压(LVSP).左室内压最大上升下降速率(±dp/dtmax)明显升高(10g±11mHg vs 70±6mmHg,P<0.01；4050±193mmHg/s vs 2959±252mmHg/s,P<0.01；3991±199mmHg/s vs 3159±190mmHg/s,P<0.01),同时左室舒张末压(LVEDP)回落(13±3mmHg vs 26±53mmHg,P<0.01).
4.与假手术组相比,心梗对照组及治疗组术后8周LVLA.LVWI、CSA显著增高(17.0±0.60mm vs 10.0±0.50mm,P<0.01、14.0±0.51mmvs 10.0±0.50mm, P<0.05；3.60±0.16mg/g vs 2.51±0.21mg/g,P<0.01；2.90±0.19mg/g vs2.51±0.21mg/g,P<0.05；718.55±87.26μm2、515.47±71.57μm2 vs 416.29±63.41μm2,P<0.01)；与心梗对照组比较,治疗组LVLA.LVWI.CSA降低(14.0±0.51mm vs 17.0±0.60mm,P<0.05；2.90±0.19mg/g vs 3.60±0.16mg/g,P<0.05；515.47±71.57μm2vs 718.55±87.26μm2,P<0.01)。
5.与假手术组相比,心梗对照组及治疗组非梗死区Ⅰ型、Ⅲ型胶原CVF、心肌细胞凋亡指数明显增高(16.45±1.32、8.79±1.06 vs 5.15±0.62,P<0.01；6.75±0.98、4.31±0.87 vs 2.16±0.55,P<0.01)；与心梗对照组比较,治疗组非梗死区工型、Ⅲ型胶原CVF、心肌细胞凋亡指数明显降低(8.79±1.06 vs16.45±1.32,P<0.01；4.31±0.87 vs 6.75±0.98,P<0.01)。
6.与假手术组相比,心梗对照组及治疗组非梗死区α-MHCmRNA表达减少,β-MHCmRNA表达增加(0.23±0.09、0.41±0.10 vs 0.61±0.12,P<0.01；2.23±0.14、1.35±0.09 vs 0.91±0.09,P<0.01)；与心梗对照组相比,治疗组非梗死区α-MHCmRNA表达增加,β-MHCmRNA表达减少(0.41±0.10 vs 0.23±0.09.P<0.05；1.35±0.09 vs 2.23±0.14,P<0.05)。
7.与假手术组相比,心梗对照组及治疗组非梗死区MMP-2、TIMP-2表达显著增加(0.45±0.0.07、0.32±0.06 vs 0.14±0.05,P<0.01；0.44±0.08、0.53±0.10 vs 0.20±0.04,P<0.01)；与心梗对照组相比,治疗组非梗死区MMP-2表达及MMP-2/TIMP-2比值降低,TIMP-2表达增加(0.32±0.06 vs0.45±0.07,P<0.05；0.81±0.07 vs 1.03±0.10,P<0.01；0.53±0.10 vs 0.44±0.08,P<0.05)。
结论：
1.瑞舒伐他汀具有改善急性心肌梗死后心室重塑、血流动力学和心功能的作用。
2.瑞舒伐他汀能够逆转心肌肌球蛋白重链基因表型改变,减轻非梗死区心肌间质胶原重构,有效防止非梗死区心肌细胞的凋亡。
3.瑞舒伐他汀下调MMP-2表达和MMP-2/TIMP-2比值,上调TIMP-2表达可能是其逆转心脏重构和改善心功能的机制之一。
Objective:To investigate the effects of Rosuvastatin on heart function, ventricular remodeling, myosin heavy chain (MHC), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in the rats of acute myocardial infarction.
Methods:Sixty Sprague-Dawley rats were randomly divided into sham operation (no coronary ligation) rats (S group, n=10) and acute myocardial infarction (AMI) rats (n=50) received a ligation of left anterior descending coronary artery.24 hours after successful modelling,36 survived rats were randomly divided into Rosuvastatin gavage group (R group, n=18) and AMI control group (M group, n=18). The rats in Rosuvastatin administration group received a gastric gavage of Rosuvastatin at 10mg/kg/d for eight weeks. The rats in AMI control group and sham operation group were give a gastric gavage of normal saline at the same dosage. Following 8-week administration, the surviving rats in each group were examined by echocardiography, hemodynamics and blood biochemical inspection. All rats were subsequently sacrificed and their hearts were taken out to detect left ventricular weight index (LVWI), left ventricular long axis (LVLA) and cross sectional area of myocardial cells(CSA). Picric acid-Sirius red staining was used to detect type I and type III collagen volume fraction (CVF) in non-infarction zone (NIZ). The index of cardiomyocyte apoptosis in NIZ was tested by TNUEL staining. The expression of MHC, MMP-2 and TIMP-2 mRNA, as well as MMP-2 and TIMP-2 protein in NIZ, were respectively measured by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry staining.
Result:
(1) There was no significant difference of serum lipid, aspartate aminotransferase (AST), creatinine (Cr) and creatine kinase (CK) among different groups.
(2) Compared with group S, the groups of M and R showed a significantly increased left ventricular end diastolic diameter (LVEDD), but a significantly decreased left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) (all P<0.05). Compared with group M, group R had a significantly decreased LVEDD, but significantly increased LVFS and LVEF(all P<0.05). (3) Compared with group S, the groups of M and R exhibited significantly decreased left ventricular systolic pressure (LVSP) and the maximum change rate of left ventricular pressure rise and fall (±dp/dtmax), but a significantly increased left ventricular end diastolic pressure (LVEDP) (all P<0.01). Compared with group M, group R showed significantly increased LVSP and±dp/dtmax, but a significantly decreased LVEDP(all P<0.01).
(4) Compared with that in group S, LVWI (P<0.05), LVLA (P<0.05) and CSA (P <0.01) significantly increased in group M and group R. Compared with that in group M, the indexes of LVWI (P< 0.05), LVLA(P< 0.05) and CSA (P< 0.01) significantly decreased in group R.
(5) Compared with that in group S, type I CVF, typeⅢCVF and the index of cardiomyocyte apoptosis in NIZ increased significantly in both groups of M and R(all P<0.01). Compared with that in group M, all these three indexes list above decreased significantly in group R(all P<0.01).
(6) Compared with that in group S, a-MHC mRNA expression significantly decreased, butβ-MHC mRNA expression significantly increased in NIZ in both groups of M and R(all P<0.01). Compared that in group M, mRNA expression of a-MHC was significantly higher butβ-MHC was significantly lower in group R(all P<0.05).
(7) Compared with that in group S, mRNA and protein expression of MMP-2 and TIMP-2 in NIZ significantly increased in both groups of M and R(all P<0.01). Compared with that in group M, mRNA and protein expression of MMP-2 and the expression ratio of MMP-2/TIMP-2 significantly decreased, but TIMP-2 expression significantly increased in group R(all P<0.05).
Conclusion:Rosuvatatin effectively improves cardiac remodeling, hemodynamics and heart function following acute myocardial infarction. It is able to reverse the phenotype change of MHC, to attenuate myocardial interstitial collagen remodeling, and to reduce cardiomyocyte apoptosis in non-infarction zone of the left ventricle. However, the improvement effects of Rosuvatatin on ventricular remodeling and heart function may be independent of its lipid-lowering function, but may be associated with its down-regulation of MMP-2 and MMP-2/TIMP-2 ratios, as well as its up-regulation of TIMP-2 expression.
引文
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