Saffitz Jeffrey E, Kléber André G
Center for Cardiovascular Research and the Department of Pathology, University of Bern, Bern, Switzerland.
Circ Res. 2004 Mar 19;94(5):585-91. doi: 10.1161/01.RES.0000121575.34653.50.
This review article focuses on remodeling of gap junctions in response to chemical mediators of ventricular hypertrophy, mechanical forces, and alterations in cell-to-cell adhesion. Signaling mediated by mechanical forces is likely to be involved in the upregulation of cardiac gap junctions during the early phase of cardiac hypertrophy and the subsequent downregulation in cardiac failure. Several signaling pathways involving cAMP, angiotensin II, transforming growth factor-beta, vascular endothelial growth factor, and integrin-mediated regulators have been shown to affect expression of gap junction proteins. However, a comprehensive view of regulation of gap junction trafficking, synthesis, and degradation is still lacking. In addition to gap junction regulation by extracellular mechanical forces, there is a close relation between gap junctions and adhesion junctions and their linkage to the cytoskeleton. This can be inferred from experiments on neoformation of cell-to-cell coupling, concomitant upregulation of adherens and gap junctions after mechanical stretch, and human cardiomyopathies caused by genetic defects in cell-cell adhesion junction proteins. The molecular mechanisms responsible for the interaction between mechanical and functional cell-to-cell coupling remain to be elucidated.
这篇综述文章聚焦于缝隙连接的重塑，以响应心室肥大的化学介质、机械力以及细胞间黏附的改变。在心脏肥大早期阶段心脏缝隙连接的上调以及随后心力衰竭时的下调过程中，机械力介导的信号传导可能参与其中。已证实涉及环磷酸腺苷（cAMP）、血管紧张素II、转化生长因子-β、血管内皮生长因子以及整合素介导的调节因子的几种信号通路会影响缝隙连接蛋白的表达。然而，对于缝隙连接运输、合成及降解调控的全面认识仍很缺乏。除了细胞外机械力对缝隙连接的调控外，缝隙连接与黏附连接之间存在密切关系，且它们与细胞骨架相联系。这可从细胞间偶联新生的实验、机械拉伸后黏附连接和缝隙连接的伴随上调以及由细胞间黏附连接蛋白的基因缺陷导致的人类心肌病中推断出来。机械与功能性细胞间偶联相互作用的分子机制仍有待阐明。
