Formigli L, Ibba-Manneschi L, Perna A M, Pacini A, Polidori L, Nediani C, Modesti P A, Nosi D, Tani A, Celli A, Neri-Serneri G G, Quercioli F, Zecchi-Orlandini S
Department of Anatomy, Histology, Forensic Medicine, University of Florence, Florence, Italy.
Histol Histopathol. 2003 Apr;18(2):359-69. doi: 10.14670/HH-18.359.
Gap-junctions are specialized regions of intercellular contacts allowing electrical impulse propagation among adjacent cardiomyocytes. Connexin43 (Cx43) is the predominant gap-junction protein in the working ventricular myocardium and its reduced expression has been extensively implicated in the genesis of conduction abnormalities and re-entry arrhythmia of chronically hypertrophied hearts. In contrast, data on the role played by this protein during cardiac remodeling and early phases of developing hypertrophy are lacking. Therefore, in the present study, we investigated this issue using an experimental model of pig left ventricle (LV) volume overloading consisting in the creation of an aorto-cava fistula. At scheduled times (6, 24, 48, 96, 168 h, and 2, 3 months after surgery) echocardiographic and haemodynamic measurements were performed and myocardial biopsies were taken for the morphological and biochemical analyses. When faced with the increased load, pig myocardium underwent an initial period (from 6 up to 48 h) of remarkable tissue remodeling consisting in the occurrence of cardiomyocyte damage and apoptosis. After that time, the tissue developed a hypertrophic response that was associated with early dynamic changes (up-regulation) in Cx43 protein expression, as demonstrated by Western blot and confocal immunofluorescence analyses. However, an initial transient increase of this protein was also found after 6 h from surgery. With the progression of LV hypertrophy (from 168 hr up to 3 months), a reduction in the myocardial Cx43 expression was, instead, observed. The increased expression of Cx43 protein during acute hypertrophic response was associated with a corresponding increase in the levels of its specific mRNA, as detected by RT-PCR. We concluded that up-regulation of Cx43 gap-junction protein could represent an immediate compensatory response to support the new working conditions in the early stages of ventricular overloading.
缝隙连接是细胞间接触的特殊区域，可使电冲动在相邻心肌细胞间传播。连接蛋白43（Cx43）是工作心室心肌中主要的缝隙连接蛋白，其表达降低与慢性肥厚心脏传导异常和折返性心律失常的发生密切相关。相比之下，关于该蛋白在心脏重塑和肥厚发展早期阶段所起作用的数据尚缺乏。因此，在本研究中，我们使用猪左心室（LV）容量超负荷的实验模型（通过建立主动脉-腔静脉瘘）来研究这个问题。在预定时间（术后6、24、48、96、168小时以及2、3个月）进行超声心动图和血流动力学测量，并取心肌活检进行形态学和生化分析。面对增加的负荷时，猪心肌经历了一个初始阶段（从6小时到48小时）的显著组织重塑，表现为心肌细胞损伤和凋亡的发生。此后，组织出现肥厚反应，这与Cx43蛋白表达的早期动态变化（上调）相关，蛋白质印迹和共聚焦免疫荧光分析证实了这一点。然而，在术后6小时也发现了该蛋白的初始短暂增加。随着LV肥厚的进展（从168小时到3个月），相反地，观察到心肌Cx43表达降低。急性肥厚反应期间Cx43蛋白表达的增加与其特异性mRNA水平的相应增加相关，这通过逆转录聚合酶链反应检测到。我们得出结论，Cx43缝隙连接蛋白的上调可能代表一种即时的代偿反应，以支持心室超负荷早期的新工作状态。
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