Di Napoli Pericle, Taccardi Alfonso A, Grilli Alfredo, Felaco Mario, Balbone Angela, Angelucci Domenico, Gallina Sabina, Calafiore Antonio M, De Caterina Raffaele, Barsotti Antonio
Laboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, Chieti, Italy.
Am Heart J. 2003 Dec;146(6):1105-11. doi: 10.1016/S0002-8703(03)00445-9.
Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Bax and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses.
We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Bax proteins were determined with both Western analysis and immunohistochemistry.
TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Bax protein were detected. The ratio of Bax to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r2 = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r2 = 0.77, P <.001 and r2 = 0.40, P <.01, respectively).
In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Bax/Bcl-2 ratio.
细胞凋亡被认为是心力衰竭（HF）发生发展的一种可能机制，但其中涉及的机制仍不清楚。在重度扩张型心肌病患者中，我们评估了心肌细胞凋亡与Bax和Bcl-2蛋白（分别为抑制或促进凋亡的两种分子）的透壁分布以及左心室壁应力的关系。
我们研究了从8例接受Batista（心室重塑）手术进行左心室减容的患者获取的90份组织样本中心肌细胞凋亡的存在及分布情况。采用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记（TUNEL）技术和DNA琼脂糖凝胶电泳，对取自整个左心室厚度（分为心外膜下、心肌中层和心内膜下部分）的组织样本进行凋亡评估。通过蛋白质免疫印迹分析和免疫组织化学法测定Bcl-2和Bax蛋白的表达。
TUNEL阳性细胞（凋亡指数）为2.3%±1.4%。凋亡细胞主要分布在心内膜下，此处检测到较高水平的Bax蛋白。Bax与Bcl-2蛋白的比值（Bax/Bcl-2）在心肌中层或心外膜下相似，但在心内膜下升高，且与收缩期壁应力直接相关（y = 0.009x - 0.629；r2 = 0.85，P <.001）。凋亡指数也与根据血流动力学和超声心动图数据计算出的收缩期和舒张末期应力直接相关（分别为r2 = 0.77，P <.001和r2 = 0.40，P <.01）。
在扩张型心肌病患者中，心肌细胞凋亡是细胞丢失的重要原因，凋亡更广泛地局限于心内膜下，且与心室壁应力和Bax/Bcl-2比值密切相关。
