Engel David, Peshock Ronald, Armstong Robert C, Sivasubramanian Natarajan, Mann Douglas L
Winters Center for Heart Failure Research, Baylor College of Medicine, and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas 77030, USA.
Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1303-11. doi: 10.1152/ajpheart.00053.2004.
Although cardiac myocyte apoptosis has been detected in explanted hearts from patients with end-stage dilated and ischemic cardiomyopathy, the relative contribution of apoptotic cell death to left ventricular (LV) remodeling and cardiac decompensation is not known. To determine whether progressive cardiac myocyte apoptosis contributes to the transition from a hypertrophic to a dilated cardiac phenotype that is observed in transgenic myosin heavy chain secreted TNF (MHCsTNF) mice with cardiac restricted overexpression of tumor necrosis factor (TNF), we assessed cardiac myocyte apoptosis (using a DNA ligase technique) in MHCsTNF mice and littermate control mice in relation to serial changes in LV structure, which was assessed using MRI. The prevalence of cardiac myocyte apoptosis increased progressively from 4 to 12 wk as the hearts of the MHCsTNF mice underwent the transition from a concentric hypertrophic to a dilated cardiac phenotype. Treatment of the MHCsTNF mice with the broad-based caspase inhibitor N-[(1,3-dimethylindole-2-carbonyl)-valinyl]-3-amino4-oxo-5-fluoropentanoic acid significantly decreased cardiac myocyte apoptosis and significantly attenuated LV wall thinning and adverse cardiac remodeling. Additional studies suggested that the TNF-induced decrease in Bcl-2 expression and activation of the intrinsic mitochondrial death pathway were responsible for the cardiac myocyte apoptosis observed in the MHCsTNF mice. These studies show that progressive cardiac myocyte apoptosis is sufficient to contribute to adverse cardiac remodeling in the adult mammalian heart through progressive LV wall thinning.
尽管在终末期扩张型和缺血性心肌病患者的移植心脏中已检测到心肌细胞凋亡，但凋亡性细胞死亡对左心室（LV）重构和心脏失代偿的相对贡献尚不清楚。为了确定在心肌特异性过表达肿瘤坏死因子（TNF）的转基因肌球蛋白重链分泌型TNF（MHCsTNF）小鼠中观察到的从肥厚型到扩张型心脏表型的转变是否由进行性心肌细胞凋亡所致，我们使用DNA连接酶技术评估了MHCsTNF小鼠和同窝对照小鼠的心肌细胞凋亡情况，并将其与通过磁共振成像（MRI）评估的LV结构的系列变化相关联。随着MHCsTNF小鼠的心脏从向心性肥厚型转变为扩张型心脏表型，心肌细胞凋亡的发生率从4周龄到12周龄逐渐增加。用广谱半胱天冬酶抑制剂N-[(1,3-二甲基吲哚-2-羰基)-缬氨酰基]-3-氨基-4-氧代-5-氟戊酸治疗MHCsTNF小鼠，可显著减少心肌细胞凋亡，并显著减轻LV壁变薄和不良心脏重构。进一步的研究表明，TNF诱导的Bcl-2表达降低和内源性线粒体死亡途径的激活是MHCsTNF小鼠中心肌细胞凋亡的原因。这些研究表明，进行性心肌细胞凋亡足以通过LV壁的进行性变薄导致成年哺乳动物心脏的不良心脏重构。
