自发性高血压大鼠心肌细胞凋亡的变化及其意义

Changes and significance of cardiac myocyte apoptosis in spontaneously hypertensive rat

目的 探讨心肌细胞凋亡在自发性高血压大鼠 (SHR)心脏重塑中的作用及其意义。方法 采用末端脱氧核糖核苷酸转移酶介导的带荧光的dUTP缺口末端标记法 (TUNEL)和透射电子显微镜技术 ,观察不同年龄SHR心肌细胞凋亡的变化及其规律。结果 (1) 1月龄SHR组 [无左室肥厚组 (NLVH组 ) ]和 18～ 2 0月龄SHR组[充血性心力衰竭组 (CHF组 ) ]凋亡的心肌细胞核数目和凋亡指数显著增加 (P均 <0 .0 1) ,10月龄SHR组 [左室肥厚组 (LVH组 ) ]则显著减少 (P均 <0 .0 1)。 (2 )有LVH的SHR中 ,心肌细胞凋亡与LVH呈显著负相关 (P <0 .0 1)。 (3 )透射电子显微镜检查发现NLVH组和CHF组SHR左心室心肌组织中可见具有凋亡形态学特征的凋亡心肌细胞 (胞质浓缩、胞核染色质浓聚边集 ) ,LVH组和CHF组可见心肌细胞肥大、肌浆网扩张和线粒体增生等改变。结论 (1)SHRLVH发生前和出现CHF后其心肌细胞凋亡显著增加 ;SHR伴显著LVH时其心肌细胞凋亡显著减少。提示心肌细胞凋亡在SHR心脏重塑中起重要作用 ,心肌细胞凋亡减少可能与LVH有关 ,而心肌细胞凋亡增多可能与CHF有关。(2 )在SHR高血压→LVH→心力衰竭演进过程中存在心肌细胞凋亡的动态变化 。

Objective To study the effects and significance of cardiomyocyte apoptosis participating in the cardiac remodeling of spontaneously hypertensive rats (SHR). Methods We investigated the dynamic changes of cardiac myocyte apoptosis in left ventricle of SHR and Wistar Kyoto rats (WKY) using in situ TdT mediated dUTP nick end labeling (TUNEL) and transmission electron microscope.Results (1)Apoptotic myocyte nuclei and apoptotic index (calculated by dividing the number of apoptotic myocyte nuclei by the total number of myocyte nuclei and multiplying that value by 100) were higher in 1 month old SHR group [no left ventricular hypertrophy (NLVH) group] and 18 20 month old SHR group [congestive heart failure (CHF) group] than those in age matched WKY group respectively (all P values less than 0.01). Apoptotic myocyte nuclei and apoptotic index were lower in 10 month old SHR [left ventricular hypertrophy (LVH) group] than those in age matched WKY group, NLVH group and CHF group (all P values less than 0.01). (2) Apoptotic index was inversely correlated with left ventricular hypertrophic index in SHR with LVH and CHF (n=6, r =-0.90, P <0.01, y=3.24 0.09x; n=5, r =-0.87, P < 0.01 , y=4.76 0.02x). (3) Electron microscopic features of cardiocyte apoptosis (including intact sarcolemma in the presence of cytoplasm compaction and segregation of nuclear chromatin into small sharply delineated electron dense masses that abut the nuclear envelope) were identified in left ventricular tissue obtained from SHR with NLVH group and CHF group but in none of the tissue specimens obtained from the left ventricles of the others. The ultramicrostructural changes, such as cardiac cellular hypertrophy, sarcoplasmic reticulum expansion, mitochondrion hyperplasia, occurred in left ventricular tissue obtained from SHR with LVH group and CHF group.Conclusion (1) Cardiac myocyte apoptosis increases significantly in the left ventricle of SHR with CHF and without LVH. However, cardiomyocyte apoptosis decreases markedly in the left ventricle of SHR with LVH. These findings suggest that cardiac myocyte apoptosis may play a key role in the heart remodeling of SHR, and that cardiomyocyte apoptosis decreasing may be bound up with LVH and cardiac myocyte apoptosis increasing may be related with CHF of SHR. (2) The dynamic changes of cardiac cell apoptosis occur in the hypertension→LVH→heart failure volving process. It is possible that the heart remodeling is ameliorated by the therapeutic strategies of stimulating or suppressing cardiomycoyte apoptosis according to the time window of cardiac cell apoptosis in the above process.