Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat
Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat
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DOI：
10.1161/01.cir.99.23.3071
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发表时间：
1999-06-15
期刊：
影响因子：
37.8
通讯作者：
Lembo, G
中科院分区：
文献类型：
--
作者：
Condorelli, G;Morisco, C;Lembo, G
左心室肥大（LVH）是对心脏工作负荷增加的适应性反应，也是心力衰竭的先兆状态。最近的证据表明，细胞凋亡导致的心肌细胞死亡与LVH和心力衰竭有关。目前还不清楚，但是，是否参与了从LVH到左心室功能不全（LVD）的过渡细胞凋亡的方法和结果心肌细胞凋亡事件和凋亡特异性基因的变化进行了研究，在大鼠模型中的慢性压力超负荷引起的横向主动脉缩窄。超声心动图评价左室构型和功能的变化。横向主动脉缩窄大鼠逐渐发展为“同心”LVH，随后发展为LVD。术后18周发现LVH和LVD的分布相似。在这个时间点，我们通过DNA梯状电泳、原位DNA TUNEL标记以及光镜和电镜观察来确定心肌细胞凋亡的发生。通过Western blot和免疫组化检测促凋亡基因和抗凋亡基因。我们的数据表明，心肌细胞凋亡事件从几乎检测不到（假手术对照组，SH）增加到LVH和LVD分别为0.8/10（3）和1.5/10（3）阳性核。LVH和LVD大鼠的内膜下和中膜区的纤维化也较SH大鼠增加。与SH相比，LVH和LVD中促凋亡基因bax的表达增加，而抗凋亡基因bcl-2的表达减少。结论这些数据表明，在对慢性压力超负荷的反应中，心肌细胞特异性凋亡有助于从LVH向LVD的转变，LVH和LVD伴随着心肌细胞促凋亡基因bax的显著上调和bcl-2/bax比值的降低，使心肌细胞易于凋亡。
Background-Left ventricular hypertrophy (LVH) represents both an adaptive response to increased cardiac work load and a precursor state of heart failure. Recent evidence linked cardiac myocyte death by apoptosis with LVH and heart failure. It remained unclear, however, whether apoptosis participated in the transition from LVH to left ventricular dysfunction (LVD).Methods and Results-Cardiac myocyte apoptotic events and changes in apoptosis-specific genes were studied in a rat model of chronic pressure overload induced by transverse aortic constriction. The changes in left ventricular geometry and function were assessed by echocardiography. Transverse aortic constriction rats progressively developed "concentric" LVH and subsequently, LVD. A similar distribution of LVH and LVD was found 18 weeks after surgery. At this time point, we determined the occurrence of myocyte apoptosis by DNA laddering, in situ DNA TUNEL labeling, and light and electron microscopy. The monitoring of proapoptotic and antiapoptotic genes was determined by Western blot and immunohistochemistry. Our data demonstrated that cardiomyocyte apoptotic events increased from virtually undetectable (in sham-operated controls, SH) to 0.8/10(3) and 1.5/10(3) positive nuclei in LVH and LVD, respectively. Fibrosis also increased in the subendocardial and midwall regions of LVH and LVD rats compared with SH. Expression of the proapoptotic gene bax increased, whereas that of antiapoptotic gene bcl-2 decreased in LVH and LVD compared with SH.Conclusions-These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD, LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene bax and reduced bcl-2/bax ratio, predisposing cardiomyocytes to apoptosis.