Activation of apoptotic caspase cascade during the transition to pressure overload-induced heart failure
Activation of apoptotic caspase cascade during the transition to pressure overload-induced heart failure
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DOI：
10.1016/j.jacc.2006.05.065
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发表时间：
2006-10-03
影响因子：
24
通讯作者：
Westaby, Stephen
中科院分区：
文献类型：
--
作者：
Moorjani, Narain;Ahmad, Manzoor;Westaby, Stephen
目的 开发压力超负荷模型来模拟主动脉瓣狭窄并评估向心力衰竭转变过程中的 caspase 活性。 背景 心肌细胞凋亡与心力衰竭的发病机制有关，而 caspase 激活是这一病理生理过程的核心。 方法 总共 10 只羊用可变主动脉缩窄装置绑扎，逐渐充气以增加左心室 (LV) 后负荷。获得连续左心室心内膜心肌活检样本，以测量半胱天冬酶活性和细胞凋亡的存在。 结果 在前 3 至 4 周内，绵羊出现肥大（左心室质量指数 90.8 +/- 4.9 g/m(2) 对比 44.0 +/- 3.0 g/m(2)，p < 0.01），随后左心室逐渐扩张（舒张期左心室内径） 4.23 +/- 0.08 厘米与 3.39 +/- 0.07 厘米，p < 0.01）。心室功能保持稳定，直到束带术后 7 至 8 周，此时出现与临床心力衰竭相关的显着恶化（缩短分数 18.3 +/- 2.4% 对比 46.9 +/- 2.6%，p < 0.01）。在每个超声心动图定义的阶段（左室肥厚、左室扩张和左室衰竭）获得连续左室心内膜心肌活检样本。 caspase-3、-8 和 -9 的活性（通过特定荧光肽底物和免疫组织化学测量）逐渐增加，特别是随着心肌功能障碍的发生（caspase-3 7.92 +/- 1.19 vs. 1.00 +/- 0.15，caspase-8 1.94 +/- 0.21 vs. 1.00 +/- 0.04，caspase-9 5.87 +/- 0.97 与 1.00 +/- 0.18 相对荧光单位，p < 0.05）。然而，免疫组织化学检测没有发现脱氧核糖核酸 (DNA) 断裂的证据。 结论 心肌细胞 caspase 酶的激活发生在向心力衰竭的转变过程中，但凋亡 DNA 断裂并未完成。 caspase-8 和 -9 活性的增加表明线粒体和死亡受体介导的途径都参与了这一病理过程。对这些途径的进一步了解可能会刺激基于细胞凋亡的策略的开发，以减缓主动脉瓣狭窄患者心力衰竭的进展。
OBJECTIVES A pressure overload model was developed to simulate aortic stenosis and assess caspase activity during the transition to heart failure.BACKGROUND Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure, and caspase activation is central to this pathophysiological process.METHODS A total of 10 sheep were banded with variable aortic constriction devices, progressively inflated to increase left ventricular (LV) afterload. Serial LV endomyocardial biopsy samples were obtained to measure caspase activity and presence of apoptosis.RESULTS Over the first 3 to 4 weeks, hypertrophy developed in the sheep (LV mass index 90.8 +/- 4.9 g/m(2) vs. 44.0 +/- 3.0 g/m(2), p < 0.01), followed by gradual dilatation of the left ventricle (diastolic LV internal diameter 4.23 +/- 0.08 cm vs. 3.39 +/- 0.07 cm, p < 0.01). Ventricular function remained stable until 7 to 8 weeks after banding, when there was significant deterioration (fractional shortening 18.3 +/- 2.4% vs. 46.9 +/- 2.6%, p < 0.01), associated with clinical heart failure. Serial LV endomyocardial biopsy samples were obtained at each echocardiographically defined stage (LV hypertrophy, LV dilation, and LV failure). Activity of caspases-3, -8, and -9 (measured by specific fluorogenic peptide substrates and immunohistochemistry) increased progressively, particularly with the onset of myocardial dysfunction (caspase-3 7.92 +/- 1.19 vs. 1.00 +/- 0.15, caspase-8 1.94 +/- 0.21 vs. 1.00 +/- 0.04, caspase-9 5.87 +/- 0.97 vs. 1.00 +/- 0.18 relative fluorescent units, p < 0.05). No evidence of deoxyribonucleic acid (DNA) fragmentation, however, was identified by immunohistochemical assays.CONCLUSIONS Activation of cardiomyocyte caspase enzymes occurs during the transition to heart failure, without completion of apoptotic DNA fragmentation. Increased activity of caspase-8 and -9 suggests both mitochondrial and death-receptor mediated pathways are involved in this pathological process. Further knowledge of these pathways may stimulate development of apoptosis-based strategies for slowing progression of heart failure in aortic stenosis patients.